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

Abstract

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 our study, 25 inverted sinonasal papillomas (ISPs), 5 oncocytic sinonasal papillomas (OSP) and 35 squamous cell carcinomas (SCCs) from 54 patients were genotyped for 10 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 ISPassociated 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 to 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.Additional Supporting Information may be found in the online version of this article. Conflict of interest: The authors declare no conflict of interest.

Significance of transcriptionally-active high-risk human papillomavirus in sinonasal squamous cell carcinoma: Case series and a meta-analysis

“…Our results demonstrated transcriptionally-active high-risk HPV in 23.5% (CI95: 10.7-41.2%) cases of SNSCC. This finding is consistent with results of 7 other studies that found proportions of transcriptionally-active HPV (by mRNA or inference from DNA and p16/ISH) in SNSCCs ranging from 11.4-31.1% [10][11][12][13][14][15][16]. Consequently, our results support the etiological role of high-risk HPV in some squamous cell carcinomas arising in sinonasal tract.…”

“…Based on the cancer registry data, which do not distinguish between transcriptionally-en CC has been reported as a favorable prognostic factor [17] or a variable not associated with survival [18]. However, only a few studies reported HPV-positivity of sinonasal carcinomas in the context of transcriptionallyactive high-risk HPV [10][11][12][13][14][15][16]. Two of these studies found significantly improved OS and DFS in HPV-positive groups [11,13], and two studies showed a trend towards better prognosis without statistical significance [14,15].…”

“…Nevertheless, studies included in these metaanalyses relied almost exclusively either on HPV DNA detection by the polymerase chain reaction (PCR), or HPV DNA by in situ hybridization (ISH), which do not distinguish between transcriptionally-infections. To date, only a limited number of studies evaluated the presence of transcriptionallyactive HPV in SNSCCs either i) directly, through the presence of HPV mRNA by PCR or ISH, or ii) by inference, through the presence of diffuse ( 70%) nuclear and cytoplasmic p16 immunostaining in tissues positive for high-risk HPV DNA as a surrogate marker [10][11][12][13][14][15][16]. In addition, prognostic significance of the HPV status in SNSCCs has not yet been conclusively established, as some investigators reported significantly better prognosis for HPV-positive cases [17], while others found no significant difference in survival between patients with HPV-positive and HPV-negative tumors [18].…”

Squamous cell carcinoma associated with inverted papilloma: Recurrence and prognostic factors

“…In recent years, some studies have Table I. reported that sinonasal IP progression to SCC was significantly associated with the presence of human papillomavirus (HPV) infection (14,15). However, Mohajeri et al compared HPV positivity among sinonasal IP samples and those from patients with SCC by immunohistochemistry and found that HPV was not supported as an etiological driver of IP development or progression to SCC (16).…”

Malignant Transformation of Schneiderian Papilloma Presenting With Progressive Binocular Diplopia and Blepharoptosis

“…The precise nature of this oncogenic transformation has not been clearly defined; thus, there is an unmet need for further studies into pathogenetic factors of SP-derived SCCs, including the ambiguous role of human papilloma virus type 16 (HPV-16) infection [5,[7][8][9]. Moreover, further evidence is warranted to support tobacco smoking as an etiological factor, despite it relates with increased risk of sinonasal SCCs and is a well-established, modifiable risk factor for head and neck cancer [10].…”