Molecular triage on HPV-positive samples in a cervical screening setting

Area of Science:

• Gynecologic Oncology
• Molecular Diagnostics
• Cervical Cancer Screening

Background:

• Current human papilloma virus (HPV) screening relies on cytology for triage, which is subjective and limited to professionally collected samples.
• Gene methylation patterns are associated with HPV-induced cervical dysplasia and cancer, suggesting potential for molecular triage.
• Developing effective molecular triage methods is crucial for improving HPV screening accuracy.

Purpose of the Study:

• To evaluate the effectiveness of molecular methods, including methylation analysis and high-risk HPV genotyping, as triage strategies for HPV-positive cervical screening samples.
• To compare the performance of these molecular methods against traditional cytology in detecting high-grade squamous intraepithelial lesions (HSIL) and cancer.

Main Methods:

• A retrospective study analyzed 1915 HPV-positive samples using FAM19A4/MiR-124-2 hypermethylation and HPV genotyping (types 16, 18, 31, 33, 45, 52, 59).
• Results were compared to cytology triage in detecting histologically confirmed HSIL and cancer from 1052 follow-up biopsies.
• Performance metrics including sensitivity, specificity, and positive predictive value (PPV) were assessed.

Main Results:

• HPV genotyping demonstrated higher sensitivity but lower specificity than cytology.
• Methylation analysis showed higher specificity but significantly lower sensitivity.
• Cytology had a PPV of 36%; molecular methods had lower PPVs, and combining them reduced sensitivity despite increasing PPV.

Conclusions:

• The evaluated molecular triage methods demonstrated reduced sensitivity compared to cytology.
• The trade-off between sensitivity and specificity does not currently support replacing cytology-based triage in Swedish cervical screening.
• Further research may be needed to optimize molecular markers for effective HPV screening triage.