What is the management plan for a 49-year-old with Atypical Squamous Cells of Undetermined Significance (ASCUS) and Human Papillomavirus (HPV) positive for E6/E7?

Management of a 49-Year-Old with ASCUS and HPV E6/E7 Positive

Colposcopy is strongly recommended for this 49-year-old patient with ASCUS and positive HPV E6/E7 mRNA test, as this combination indicates a significantly higher risk for progression to high-grade cervical lesions. 1, 2

Risk Assessment and Rationale

The presence of HPV E6/E7 mRNA positivity in a patient with ASCUS is particularly concerning because:

• E6/E7 mRNA detection indicates active viral oncogene expression, which is associated with a higher risk of progression to CIN2+ (cervical intraepithelial neoplasia grade 2 or worse) 2
• Women with ASCUS who are HPV positive have a 9.7% risk of harboring CIN2+ 1
• Research shows that women positive for HPV E6/E7 mRNA have a 3.08 times higher risk of progressing to CIN2+ within 2 years compared to those who are negative 3

Management Algorithm

1. Immediate colposcopy with endocervical sampling

   • Colposcopy is the preferred management for women with ASCUS who are HPV positive 1
   • Endocervical sampling is preferred for women in whom no lesions are identified (BII) and those with an unsatisfactory colposcopy (AII) 1

2. If colposcopy is satisfactory and no CIN is identified:

   • Follow-up with either:
     • HPV DNA testing at 12 months, OR
     • Repeat cytology at 6 and 12 months 1
   • Referral to colposcopy is recommended if subsequent HPV test is positive or if repeat cytology shows ASC-US or greater 1

3. If CIN is identified on colposcopy:

   • For CIN 1: Follow-up with either HPV DNA testing at 12 months or repeat cytology at 6 and 12 months 1
   • For CIN 2/3: Treatment with excision (LEEP, cold knife conization) or ablation (laser, cryotherapy) is recommended 1

Important Considerations

• Age factor: At 49 years old, this patient has a higher risk of persistent HPV infection and progression to high-grade lesions compared to younger women 1
• E6/E7 significance: The presence of E6/E7 mRNA is particularly concerning as it indicates active expression of viral oncogenes that directly interfere with cell cycle regulation 2, 3
• Avoid diagnostic excisional procedures without histologic confirmation: The routine use of diagnostic excisional procedures such as LEEP is unacceptable for women with initial ASC-US in the absence of histologically diagnosed CIN 2/3 1

Follow-up After Initial Management

• If HPV DNA test is negative at 12-month follow-up or if two consecutive repeat cytologic tests are negative, return to routine screening is recommended 1
• If HPV DNA test is positive or if repeat cytology shows ASC-US or greater, colposcopy is recommended 1

Pitfalls to Avoid

• Do not delay evaluation: E6/E7 mRNA positivity indicates active viral oncogene expression and higher risk of progression, requiring prompt evaluation 2
• Do not perform HPV testing at intervals less than 12 months: This is explicitly not recommended (EIII) 1
• Do not rely on HPV 16/18 genotyping alone: For women with ASC-US who are positive for oncogenic HPV, the NCCN and ASCCP do not recommend using HPV 16/18-specific DNA testing as a screen to determine who should proceed to colposcopy 1
• Avoid overtreatment: Diagnostic excisional procedures should not be performed without histologic confirmation of high-grade disease 1

The presence of HPV E6/E7 mRNA in this 49-year-old patient with ASCUS significantly increases her risk for harboring or developing high-grade cervical lesions, making prompt colposcopic evaluation essential for appropriate management and prevention of potential progression to cervical cancer.