What is the management plan for a patient with a normal Pap (Papanicolau) smear but positive Human Papillomavirus (HPV) status with an unknown genotype, absence of high-risk types 16, 18, and 45, and no E6/E7?

Management of Normal Pap with HPV-Positive (Non-16/18/45, E6/E7 Negative)

For a patient with normal Pap cytology but positive for high-risk HPV (excluding types 16,18, and 45, with negative E6/E7), repeat co-testing (HPV and cytology) at 12 months is the recommended management strategy, with colposcopy reserved only if HPV remains positive or cytology becomes abnormal at follow-up. 1, 2

Rationale for Conservative Management

The key distinction here is that your patient does NOT have HPV 16,18, or 45—the highest-risk genotypes that warrant immediate colposcopy regardless of cytology. 1, 3

• Risk stratification matters: Women with non-16/18 high-risk HPV types have only a 1.5-3% risk of CIN 3+ lesions, which falls below the threshold for immediate colposcopy. 2
• In contrast, HPV 16 or 18 positive patients have a 17-21% 10-year cumulative risk of CIN 3+, justifying immediate colposcopy even with normal cytology. 2
• The absence of E6/E7 mRNA expression further supports conservative management, as E6/E7 transcripts are strongly associated with high-grade lesions (OR = 106.12 for CIN2+ when mRNA positive). 4

Recommended Management Algorithm

Initial approach:

• Schedule repeat co-testing (both HPV and cytology) at 12 months from the initial positive HPV result. 1, 2
• Do NOT perform immediate colposcopy for this patient population. 2
• Approximately 60% of high-risk HPV infections clear spontaneously within one year, making watchful waiting appropriate. 2

At 12-month follow-up:

• If both HPV and cytology are negative: Return to routine age-based screening (typically every 3 years for co-testing). 1, 2
• If HPV remains positive (regardless of cytology): Proceed to colposcopy with endocervical sampling. 1, 2
• If cytology shows any abnormality (regardless of HPV status): Proceed to colposcopy according to cytology-based management guidelines. 1, 2

Follow-Up Testing Preferences

• HPV testing or co-testing is strongly preferred over cytology alone for follow-up after an abnormal result, as negative HPV testing is less likely to miss disease than normal cytology alone. 1, 5
• The CDC specifically recommends HPV testing or co-testing over cytology-only approaches for surveillance. 1

Critical Pitfalls to Avoid

Do not perform immediate colposcopy for women with negative cytology but positive non-16/18 high-risk HPV—this represents overtreatment and increases unnecessary procedures, costs, and patient anxiety. 2

Do not use HPV genotyping for further triage in women already confirmed negative for HPV 16/18—additional genotyping provides no clinical benefit in this scenario. 2

Do not perform treatment based on HPV result alone without histologic confirmation of disease if colposcopy is eventually performed. 2

Do not rely solely on repeat cytology without HPV testing for follow-up, as this misses the superior negative predictive value of HPV testing. 5

If Colposcopy Becomes Necessary

Should your patient require colposcopy at the 12-month follow-up (due to persistent HPV or abnormal cytology):

• Perform thorough examination of the transformation zone with acetic acid and Lugol's iodine. 5
• Obtain directed biopsies of any suspicious areas. 5
• Consider endocervical sampling, particularly given the association of some high-risk HPV types with adenocarcinoma. 1, 5

Post-colposcopy management:

• If colposcopy and biopsy are negative, repeat HPV testing or co-testing at 12 months. 5
• If CIN 2+ is detected, treatment options include ablative or excisional procedures, with surveillance continuing for at least 25 years post-treatment. 1, 5