I have a positive high‑risk HPV mRNA (E6/E7) test from routine cervical screening; what does this indicate and how should it be managed based on my cytology results and age?

Management of Positive High-Risk HPV mRNA E6/E7 Test

A positive high-risk HPV mRNA E6/E7 test indicates active viral oncogene expression and requires immediate colposcopy regardless of cytology results, as this marker identifies women at substantially higher risk for high-grade cervical intraepithelial neoplasia (CIN 2/3) compared to HPV DNA testing alone. 1, 2

What This Test Result Means

A positive HPV E6/E7 mRNA test is fundamentally different from a positive HPV DNA test:

• E6/E7 mRNA detection indicates active viral oncogene transcription, which is necessary for malignant transformation and maintenance of the neoplastic state 3, 2
• This test has 97% concordance with HPV DNA types but identifies a subset of infections with true oncogenic activity 2
• The sensitivity for detecting histologically-proven CIN 3 lesions is 95% with a negative predictive value of 86-90% 2, 4
• E6/E7 mRNA positivity correlates better with lesion severity than HPV DNA testing alone 1, 3

Risk Stratification by Age and Cytology

Women ≥35 Years of Age

In women over 35 years, E6/E7 mRNA positivity is a strong predictor of persistent disease and progression:

• The frequency of HSIL/LSIL cytology in mRNA-positive patients over 35 is significantly higher at both 1-year and 2-year follow-up compared to mRNA-negative patients 5
• Detection rates increase with lesion severity: CIN 0 (18%), CIN I (58%), CIN II (77%), CIN III (84%) 3
• Proceed directly to colposcopy regardless of cytology results 6

Women <35 Years of Age

• The natural history of HPV infection differs in younger women, with higher spontaneous regression rates 5
• E6/E7 mRNA positivity does not show the same predictive value for progression in women under 35 5
• Management should still follow standard colposcopy protocols for positive high-risk HPV results 6

Immediate Management Algorithm

Step 1: Colposcopy Referral

All women with positive E6/E7 mRNA should undergo colposcopy with the following protocol:

• Visualize the entire transformation zone (required for satisfactory colposcopy) 7
• Obtain directed biopsies from any suspicious lesions 7
• Perform endocervical sampling, particularly if no lesions are identified or if colposcopy is unsatisfactory 6, 7

Step 2: Management Based on Biopsy Results

If CIN 2 or CIN 3 is identified:

• Treatment with excisional procedures (LEEP or cold-knife conization) or ablative procedures is indicated 6, 8
• Histologic confirmation is required before excisional procedures 7
• CIN 2 may be followed without treatment only in select young women desiring fertility who are reliable with follow-up 6, 8

If CIN 1 or negative biopsy:

• Two acceptable options exist: repeat HPV testing at 12 months, or repeat cytology at 6 and 12 months 6, 7
• If repeat cytology shows ≥ASC-US, proceed to colposcopy 6
• If HPV remains positive at 12 months, proceed to colposcopy 6

Post-Treatment Surveillance

For women treated for CIN 2 or CIN 3:

• Surveillance must continue for at least 25 years after treatment, even extending past age 65 8, 9
• Initial post-treatment testing includes HPV test or co-test at 6,18, and 30 months 9, 8
• Long-term surveillance includes testing at 3-year intervals if using HPV testing or co-testing 9

Critical Pitfalls to Avoid

• Do not delay colposcopy based on normal cytology alone when E6/E7 mRNA is positive 8, 7
• Do not perform treatment based on mRNA results alone without histologic confirmation 8
• Do not use E6/E7 mRNA testing for deciding whether to vaccinate, screening for genital warts, or in women <25 years as routine screening 9
• Do not discontinue surveillance early after treatment for high-grade lesions; the 25-year surveillance period is mandatory 9, 8

Patient Counseling

Frame the discussion in a neutral, non-stigmatizing manner:

• HPV infections are extremely common in sexually active individuals 8
• E6/E7 mRNA positivity indicates the virus is actively expressing oncogenes, requiring closer monitoring 1, 2
• Most infections can be successfully treated when detected early 8
• Adherence to follow-up appointments is essential, as missed visits leave women at higher risk for progression 9
• HPV can remain dormant for years; detection does not imply recent infection or infidelity 6

Evidence Quality and Nuances

The E6/E7 mRNA test represents a more specific marker than HPV DNA testing alone, with research showing 88.9% sensitivity and 97.5% specificity for detecting cervical abnormalities 4. While older guidelines 6 focus on HPV DNA testing, emerging evidence 5, 1, 2, 4 demonstrates that E6/E7 mRNA detection identifies a subset of infections with true oncogenic activity. The prognostic power for predicting disease progression shows 78% sensitivity and 90% negative predictive value 2, making this a clinically useful biomarker particularly in women over 35 years of age 5.