What are the next steps for a sexually active female patient with a positive Human Papillomavirus (HPV) test that does not reflex, and no prior history of cervical cancer or high-grade cervical dysplasia?

Management of HPV-Positive Test Without Reflex Cytology

Immediate Next Step

Order reflex cytology from the same specimen if still available, or have the patient return for cytology testing to guide appropriate management. 1, 2

The 2021 CDC STI Treatment Guidelines explicitly state that when primary HPV testing is used for screening, cytology testing should be performed for all positive HPV test results to help determine the next steps in management, ideally as a reflex test from the same specimen so the patient does not need to return to the clinic. 1

Management Algorithm Based on Cytology Results

If Cytology Shows HSIL (High-Grade Squamous Intraepithelial Lesion)

• Proceed directly to colposcopy with consideration for expedited treatment (excision without prior biopsy) for non-pregnant patients aged ≥25 years. 1
• Colposcopy with biopsy is an acceptable alternative if preferred after shared decision-making. 1

If Cytology Shows ASC-US or LSIL

• Proceed directly to colposcopy as the combination of HPV positivity with any cytologic abnormality significantly elevates risk of high-grade CIN (approximately 20% risk of CIN2+ and 9.7% risk of CIN3+). 2
• The American Society for Colposcopy and Cervical Pathology recommends immediate colposcopy rather than surveillance for HPV-positive ASC-US or LSIL. 2

If Cytology is Normal (NILM)

• Check HPV genotyping for types 16 and 18:
  • If HPV 16 positive: Proceed directly to colposcopy (HPV 16 is the highest-risk type with 17% risk of CIN3+). 1, 2
  • If HPV 18 positive: Proceed directly to colposcopy with consideration for endocervical sampling due to association with adenocarcinoma (14% risk of CIN3+). 1, 2
  • If other high-risk HPV types (not 16/18): Return in 1 year for repeat HPV testing or co-testing. 1

Important Clinical Context

Why Reflex Cytology Matters

• The 2004 NCCN guidelines noted that "reflex cytology mechanisms are not current practice" at that time, but emphasized their importance for post-colposcopy decision-making. 1
• Current 2021 CDC guidelines have now made reflex cytology the standard of care for primary HPV screening. 1
• Without cytology results, you cannot appropriately risk-stratify this patient or determine whether immediate colposcopy is needed versus surveillance. 1, 2

Risk Stratification Considerations

• HPV positivity alone carries variable risk depending on HPV type: HPV 16 (17% CIN3+ risk), HPV 18 (14% CIN3+ risk), other high-risk types (3% CIN3+ risk). 2
• The combination of HPV positivity with abnormal cytology creates substantially higher risk than either finding alone. 2
• Analysis from the ALTS trial showed that HPV-positive ASC-US and LSIL carry equal 26% cumulative risk of CIN2-3 over 2 years. 1

Common Pitfalls to Avoid

• Do not proceed directly to colposcopy without knowing cytology results unless it is infeasible for the patient to return for cytology testing alone, in which case colposcopy can be considered. 1
• Do not delay obtaining cytology results as this represents incomplete screening that cannot be properly managed according to current guidelines. 1, 2
• Do not assume low risk based on HPV positivity alone without knowing the specific HPV type or cytology results. 2
• Do not order HPV genotyping before obtaining cytology as the cytology result is the primary determinant of immediate management. 1

Age-Specific Considerations

• For this sexually active female patient, if she is aged 30-65 years, HPV positivity is more concerning and less likely to represent transient infection compared to younger women. 2
• Women aged 30+ with HPV-positive abnormal cytology have higher risk of underlying significant disease requiring colposcopy. 2