Comprehensive analysis of HPV infection, EGFR exon 20 mutations and LINE1 hypomethylation as risk factors for malignant transformation of sinonasal inverted papilloma to squamous cell carcinoma

Different risk factors are suspected to be involved in malignant transformation of sinonasal papillomas and include HPV infection, tobacco smoking, occupational exposure, EGFR/KRAS mutations and DNA methylation alterations. In this study, 25 inverted sinonasal papillomas (ISPs), 5 oncocytic sinonasal papillomas (OSP) and 35 squamous cell carcinomas (SCCs) from 54 patients were genotyped for ten genes involved in EGFR signalling. . HPV‐DNA detection was performed by in‐situ hybridisation and LINE‐1 methylation was quantitatively determined by bisulphite‐pyrosequencing.

High‐risk HPV was observed only in 13% of ISP‐associated SCC and in 8% of de novo‐SCC patients. EGFR mutations occurred in 72% of ISPs, 30% of ISP‐associated SCCs and 17% of de novo‐SCCs. At 5‐year follow‐up, SCC arose in only 30% (6/20) of patients with EGFR‐mutated ISPs compared with 76% (13/17) of patients with EGFR‐wild‐type ISP (p=0.0044). LINE‐1 hypomethylation significantly increased from papilloma/early stage SCC to advanced stage SCC (p=0.03) and was associated with occupational exposure (p=0.01) and worse prognosis (p=0.09). In conclusion, our results suggest that a small subset of these tumours could be related to HPV infection; EGFR mutations characterise those ISPs with a lower risk of developing into SCC; LINE‐1 hypomethylation is associated with occupational exposure and could identify more aggressive nasal SCC.

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