What are the next steps for a 45-year-old female with a normal Pap (Papanicolau) smear but positive Human Papillomavirus (HPV) test?

Management of 45-Year-Old Female with Normal Pap Smear and Positive HPV Test

For a 45-year-old female with normal Pap smear but positive HPV test, the recommended management is to perform repeat co-testing (Pap and HPV test) in 12 months to determine if the HPV infection will clear spontaneously. 1

Initial Assessment and Risk Stratification

The finding of a normal Pap smear with positive HPV test (also known as HPV-positive/cytology-negative) requires careful follow-up due to the increased risk of developing cervical intraepithelial neoplasia (CIN) or cancer over time. This combination represents a significant clinical scenario that warrants structured management:

1. HPV Genotyping (if available):

   • If HPV testing identifies types 16 or 18 specifically, immediate colposcopy is indicated due to higher risk of progression 1
   • For other high-risk HPV types, follow the repeat testing protocol below

2. Standard Management Protocol:

   • Repeat co-testing (both Pap and HPV test) in 12 months 1, 2
   • This approach allows time to determine if the HPV infection will clear spontaneously, which occurs in many cases

Follow-Up Based on 12-Month Co-Test Results

The management pathway branches based on the results of the 12-month follow-up testing:

• If both tests are negative (normal Pap and negative HPV):

  • Return to routine age-appropriate screening 1
  • The negative predictive value of HPV testing is extremely high (99.6% for HSIL) 3

• If HPV test remains positive OR cytology shows ASC-US or greater:

  • Refer for colposcopy 1
  • This approach has been shown to correctly identify 92% of women with biopsy-proven CIN 4

• If two consecutive positive HPV tests (even with normal cytology):

  • Colposcopy is indicated 1
  • This indicates persistent HPV infection, which significantly increases risk for cervical neoplasia

Evidence Strength and Clinical Considerations

The recommended approach is supported by high-quality evidence:

• The 2025 Cervical Cancer Screening Guidelines from ACOG rate the strength of evidence for this management approach as high 1
• A 2004 consensus workshop by the NIH-NCI, ASCCP, and American Cancer Society established that women with negative cytology but positive HPV are at relatively low immediate risk but require structured follow-up 2
• A 2012 study evaluating 14 triage strategies found that cytology triage followed by repeat cytology testing yielded a high negative predictive value (99.3%) with a modest colposcopy referral rate (33.4%) 5

Common Pitfalls to Avoid

1. Immediate colposcopy for all HPV-positive results:

   • Not recommended for normal cytology with HPV-positive results (except for HPV 16/18)
   • Leads to unnecessary procedures and potential overtreatment 2

2. Inadequate follow-up:

   • Studies show compliance with recommended follow-up can be low (45.1%) 3
   • Clear documentation and patient education about the importance of the 12-month follow-up is essential 1

3. Misinterpreting test results:

   • Quality assurance reviews have found that a small percentage (0.4%) of HPV-positive/cytology-negative cases may be reclassified upon review 6
   • This emphasizes the importance of proper testing technique and interpretation

4. Extending screening intervals too soon:

   • The 3-year extended screening interval only applies to women with both normal Pap and negative HPV 1
   • HPV-positive results require the structured follow-up described above

By following this evidence-based approach, clinicians can appropriately manage the finding of normal Pap with positive HPV in a 45-year-old woman, balancing the need for adequate surveillance with avoiding unnecessary interventions.