What is the next step for a patient in their 30s with a Pap (Papanicolau) smear showing Atypical Squamous Cells of Undetermined Significance (ASCUS) and positive for high-risk Human Papillomavirus (HPV) types E6 and E7?

Management of ASCUS with HPV E6/E7 Positive in a Patient in Their 30s

Proceed directly to colposcopy with colposcopically-directed biopsies—this is the definitive next step for any patient aged 30 or older with ASCUS cytology and positive high-risk HPV testing. 1, 2

Rationale for Immediate Colposcopy

• The combination of ASCUS with HPV positivity significantly elevates the risk of underlying high-grade cervical intraepithelial neoplasia (CIN 2+), with approximately 20% risk of CIN 2+ and 9.7% risk of CIN 3+ in this population. 2

• The American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines explicitly state that colposcopy is indicated for evaluating women with abnormal results when there are positive HPV test results and ASCUS or worse. 1

• HPV E6/E7 mRNA positivity is particularly concerning, as women positive for E6/E7 mRNA have a significantly greater risk of malignant progression of cervical lesions compared to those who are E6/E7 mRNA negative. 3

• At age 30+, HPV positivity is more concerning and less likely to represent transient infection, with a higher risk of underlying significant disease compared to younger women. 2

Why Not Alternative Approaches

• Do not perform repeat cytology or HPV testing as the initial management strategy—this approach has lower sensitivity (76.2%) compared to immediate colposcopy and delays diagnosis of high-grade disease. 2

• Do not perform HPV 16/18 genotyping before colposcopy, as colposcopy is indicated regardless of specific HPV type when ASCUS is combined with any high-risk HPV positivity. 1, 2

• Conservative management with repeat testing is only appropriate for younger women (ages 21-24) where cancer risk is lower—this patient in their 30s requires more aggressive evaluation. 1

The Colposcopy Procedure

• During colposcopy, the cervix is examined using magnification (10x-16x) after application of 3-5% acetic acid solution, which allows visualization of abnormal areas and directed biopsies. 1

• If the entire squamocolumnar junction is visualized (adequate colposcopy), endocervical curettage is not required. 1

• If colposcopy is unsatisfactory (transformation zone not fully visualized), perform endocervical curettage in addition to cervical biopsy. 2

Management Based on Colposcopy Findings

• If CIN 2 or higher is detected: Proceed with appropriate treatment (excisional procedures like LEEP or cold-knife conization, or ablative procedures like laser ablation or cryotherapy). 1, 2

• If CIN 1 or less is detected: Follow surveillance protocols with repeat HPV testing or co-testing at 1 year. 2

• If no lesion is identified: Repeat HPV testing with or without concurrent Pap test in 1 year. 2

Critical Pitfalls to Avoid

• Do not delay colposcopy in HPV-positive ASCUS cases in women over 30—this increases the risk of missed high-grade disease and potential progression to invasive cancer. 2

• Do not assume low risk despite ASCUS being a relatively mild cytologic abnormality; the combination with HPV positivity (especially E6/E7 mRNA) significantly increases risk. 2, 3

• Do not rely on the fact that HPV testing has lower specificity (72-79%) as a reason to defer colposcopy—the high sensitivity (88-90%) for detecting high-grade lesions makes it the appropriate triage test. 2

• Be aware that loss to follow-up rates can be high (27-48% in some studies), making immediate definitive evaluation even more critical. 4