The Role of Integration and HPV Status in Malignant Transformation of Inverted Papillomas

Introduction: Inverted papillomas (IPs) are rare, benign, sinonasal tumors with the ability to undergo malignant transformation. While rare, they are the most common type of papilloma within the sinonasal cavity and represent up to 5% of primary nasal cavity tumors. There have been many studies attempting to define a causal link between HPV and malignant transformation of IPs with mixed results. Additionally, these tumors have a high recurrence rate, and their malignant transformation potential has spurred significant investigation into their etiology, disease course, and treatment. Prior meta-analyses of HPV-mediated transformation of IPs have suggested a nearly 50% prevalence of HPV in IPSCC and strong bias toward the high-risk virus types, HPV16 and HPV18, in IP malignant transformation. In this study, we have identified a large, retrospective cohort of benign IPs, IP-SCC, and control sinonasal polyp tissues that have been tested for high-risk HPV types to determine the prevalence in both benign and malignant IPs.

Methods: A total of 94 IP tumors, 22 IP-SCC, and 13 sinonasal polyps were stained with HPV16/18 RNAscope and imaged with fluorescence to determine HPV status. Formalin-fixed slides were processed via standard antigen retrieval protocols and anti-HPV RNA staining was performed. Imaging was performed via confocal and bright-field microscopy.

Results: We demonstrated significant HPV-positivity in IP-SCC versus benign IP tumors (p < 0.05). HPV-RNA levels in IP-SCC tumors were significantly higher than those in benign HPV-positive tumors (p < 0.05). Additionally, we identified HPV integration occurred at a higher rate in IP-SCC than in benign IP tumors.

Conclusion: HPV status in IP surgery has long been inconclusive with respect to malignant transformation. Our data suggest that malignant IPs have a higher incidence of HPV-positivity, higher HPV RNA levels, and higher incidence of HPV integration. These data could indicate that HPV RNA activity and integration status could portend higher likelihood of malignant transformation in IPs.