What are the next steps for a patient with detected Human Papillomavirus (HPV) messenger RNA (mRNA) E6/E7?

Management of HPV mRNA E6/E7 Positive Results

For patients with detected HPV mRNA E6/E7, immediate referral for colposcopy is strongly recommended as this indicates active oncogenic HPV infection with higher risk of cervical intraepithelial neoplasia or invasive cancer. 1

Understanding the Significance

HPV E6/E7 mRNA detection is a more specific marker for oncogenic activity than standard HPV DNA testing. While HPV DNA testing simply identifies the presence of the virus, E6/E7 mRNA detection specifically identifies transcriptionally active HPV infections where the oncogenes are being expressed, indicating:

• Higher risk of progression to cervical intraepithelial neoplasia (CIN) and invasive cancer 2
• Better correlation with lesion severity compared to HPV DNA testing 3
• Active expression of oncoproteins that drive carcinogenesis 4

Management Algorithm

Immediate Steps:

1. Refer for colposcopy - This is mandatory regardless of cytology results 1

   • Colposcopy should be performed by a clinician experienced in examining the lower genital tract and performing colposcopically directed biopsies
   • For HPV types 16 and 18, colposcopy is recommended even with normal cytology due to their high oncogenic potential

2. Perform cytology testing if not already done

   • Ideally as a reflex test from the same specimen
   • Results will help determine further management steps 1

Based on Colposcopy and Cytology Results:

If Colposcopy Shows Abnormal Findings:

• Biopsy all suspicious lesions
• If CIN2+ or AIS is identified:
  • For non-pregnant patients ≥25 years: Expedited treatment is preferred 1
  • Treatment options include LEEP or cold knife conization (CKC)
  • CKC is preferred for suspected adenocarcinoma in situ (AIS) 1

If Colposcopy is Normal or Shows CIN1:

• If HPV type is 16 or 18: Close follow-up with repeat colposcopy in 6-12 months 1
• If other high-risk HPV types: Return in 1 year for repeat HPV testing and cytology 1

Post-Treatment Surveillance

For patients treated for high-grade precancer (CIN2+):

• Initial surveillance: HPV test or cotest at 6,18, and 30 months 1
• Long-term surveillance: Continue testing every 3 years for at least 25 years 1
• If using cytology alone: Testing at 6,12,18,24, and 30 months, then annually 1

Special Considerations

For Patients with AIS:

• Consider referral to a gynecologic oncologist 1
• Hysterectomy is the definitive treatment
• For patients desiring fertility preservation:
  • CKC with negative margins may allow conservative follow-up
  • Counsel on 30% risk of residual disease despite negative margins 1

For Patients with Atypical Glandular Cells (AGC):

• More comprehensive evaluation is needed including:
  • Colposcopy
  • Endocervical curettage (ECC)
  • HPV DNA testing
  • Endometrial biopsy for patients ≥35 years or with risk factors for endometrial cancer 1

Clinical Pitfalls to Avoid

1. Do not delay colposcopy - HPV E6/E7 mRNA positivity indicates active oncogenic expression
2. Do not rely solely on cytology - Normal cytology does not rule out significant lesions in E6/E7 positive patients
3. Do not use LEEP for AIS without careful consideration - Higher rates of positive margins compared to CKC 1
4. Do not discontinue surveillance too early after treatment - Continue for at least 25 years 1
5. Do not assume negative margins rule out disease - 30% of AIS patients with negative margins have residual disease on hysterectomy 1

HPV E6/E7 mRNA testing has demonstrated superior specificity (88.6% vs 48.1%) compared to HPV DNA testing in identifying clinically relevant infections 5. Research has shown that patients positive for HPV E6/E7 mRNA have significantly higher rates of high-grade lesions and invasive cancer compared to those with only HPV DNA positivity 3.