EGFR mutations in sinonasal squamous neoplasms: Novel hotspot for exon 20 insertions

EGFR mutations and oncogenic high-risk (HR) HPV have been suggested to be mutually exclusive pathways in pathogenesis of sinonasal squamous neoplasms which include sinonasal papilloma and squamous cell carcinoma (SCC). In Indian patients, HR-HPV association is rare; however, there is no data on EGFR mutations in these tumors. One-hundred-eleven cases of sinonasal squamous neoplasms were interrogated for EGFR exon 19 and 20 mutations, including 48 inverted papillomas (IP), 15 SCC arising in the background of inverted papilloma (IP-SCC) and 48 de novo SCC. HR-HPV association was determined by p16 immunohistochemistry, followed by mRNA in situ hybridization (ISH) in all p16 positive and a subset of negative cases. Low-risk (LR)-HPV mRNA ISH was performed in all EGFR wild-type IP and IP-SCC. Among 94 cases with valid results (41 IP, 10 IP-SCC and 43 de novo SCC), EGFR mutations were identified in 24 (59%) IP, 4 (40%) IP-SCC and 15 (35%) de novo SCC. EGFR mutations were associated with nasal cavity location and non-keratinizing histology. All exon 20 insertions were located between residues 778 and 810. p16 immunopositivity was present in 18 cases, including 7 EGFR mutant ones. mRNA ISH identified HR-HPV in one p16 positive de novo SCC, which also had an EGFR mutation. LR-HPV was absent in all 34 cases tested. Thus, we identified EGFR exon 20 mutations at a novel hotspot in a sizeable number of sinonasal squamous neoplasms, both IPs and SCCs, suggesting that they play a significant role in their pathogenesis. Exon 19 mutations were uncommon.