Negative PAP with Positive hrHPV: Implications of Prevalence of hrHPV Types for Referral to Colposcopy

Summary: Introduction: Persistent infection with high-risk HPV (hrHPV), notably HPV16 and 18 causes about 70% cervical cancer cases. Screening is done through primary hrHPV testing or cervical cytology (PAP) with hrHPV co-testing for women aged ≥30 years. ASCCP guidelines recommend reflex cytology (Papanicolaou test - PAP) for women with positive primary hrHPV screening, regardless of genotype. However, this may miss women with negative PAP who may be harboring HSIL. The optimal approach for women with negative PAP and non16/18 hrHPV (other hrHPV) strains is still debated. We analyzed data from women with negative PAP who underwent HPV co-testing to determine HSIL+ frequency. Materials and Methods: Surgical pathology data from 1137 women aged ≥30 years with negative PAP and hrHPV co-testing was collected retrospectively between July 2021 and July 2023. hrHPV results were categorized into negative, HPV16, HPV18, other hrHPV (including HPV 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) and co-infection (HPV16/18 with other hrHPV) groups. Histopathology outcomes were classified as benign, LSIL, HSIL, and carcinoma (Table 1). Results: Negative hrHPV group was associated with a reduced likelihood of SIL (LSIL and HSIL) compared to all hrHPV positive groups except for HPV 18 group. Interestingly, the single case of SCC was hrHPV negative. Among hrHPV-positive groups, other hrHPV was the most prevalent and was associated with a higher likelihood of HSIL compared to the HPV-negative group and a lower likelihood of HSIL compared to the HPV16 group. No significant difference in the likelihood of HSIL was observed when other hrHPV group was compared to HPV18 and co infection groups (Table 2). Conclusions: In our study, other hrHPVs were the most prevalent hrHPV types in women with negative PAP and positive hrHPV. While HPV 16/18 prompts colposcopy in women with negative PAP, HPV 18 did not show higher LSIL or HSIL+ risk compared to the other hrHPV group. These findings challenge current colposcopy guidelines based on hrHPV types for women with negative PAP.