The presence of high-risk human papillomavirus (HPV) E6/E7 mRNA transcripts in a subset of sinonasal carcinomas is evidence of involvement of HPV in its etiopathogenesis

Abstract

The aim of the study was to investigate prevalence of high-risk human papillomavirus (HR-HPV) infection in sinonasal carcinomas by immunohistochemistry, in situ hybridization, and polymerase chain reaction, detecting p16(INK4a) protein (p16) expression and presence of both HPV DNA and HPV E6/E7 messenger RNA (mRNA). The study comprised 47 males and 26 females, aged 23-83 years (median 62 years), mostly (67 %) with a squamous cell carcinoma (SCC). Of the tumors, 53 % arose in the nasal cavity, 42 % in the maxillary sinus, and 5 % in the ethmoid complex. The follow-up period ranged 1-241 months (median 19 months). HPV16, HPV18, or HPV35 were detected in 18/73 (25 %) tumors, 17 SCCs, and 1 small cell neuroendocrine carcinoma. There was a strong correlation between results of HPV detection methods and p16 expression (p < 0.005). HPV-positive SCCs occurred more frequently in smokers (p = 0.04) and were more frequently p16-positive (p < 0.0001) and nonkeratinizing (p = 0.02), the latter occurring more commonly in nasal cavity (p = 0.025). Median survival for HPV-positive SCC patients was 30 months, while for HPV-negative SCC patients was 14 months (p = 0.23). In summary, we confirm that HR-HPV is actively involved in the etiopathogenesis of a significant subset of sinonasal SCCs. p16 may be used as a reliable surrogate marker for determination of HPV status also in sinonasal SCCs. Although we observed a trend toward better overall survival in HPV-positive SCCs, the prognostic impact of HPV status in sinonasal carcinomas needs to be elucidated by further studies.

HPV-related Multiphenotypic Sinonasal Carcinoma

“…(19, 20) Furthermore, the sinonasal tract has been identified as another “hot spot” for HPV-related carcinomas, with 20-25% of sinonasal carcinomas harboring transcriptionally active high-risk HPV. (3-7) In the sinonasal tract, HPV positivity usually is associated with non-keratinizing squamous cell carcinoma, but we have previously drawn attention to a peculiar form of HPV-related sinonasal carcinoma characterized by a component of cribriforming growth and a strong tendency to be misclassified as high grade adenoid cystic carcinoma. (8) Since its initial description in 2012 under the term “HPV-related carcinoma of the sinonasal tract with adenoid cystic-like features,” just a handful of additional cases have been reported, and it was only provisionally included in the WHO classification of head and neck tumors (as a form of non-keratinizing squamous cell carcinoma).…”

“…Even compared to other sinonasal carcinomas (both HPV-positive and HPV-negative), this behavior appears to be uniquely indolent. (4, 5, 7) These observations would seem to justify a therapeutic approach that would include surgical resection of the primary tumor followed by radiation therapy for close or positive margins. In the absence of documented regional or distant disease, routine lymph node dissection and chemotherapy do not appear to be indicated for HMSC although our experience with these tumors is still too limited for any definitive treatment conclusions.…”

“…(1) Although most HPV-related head and neck carcinomas arise from the oropharynx,(2) the sinonasal tract represents another anatomic “hot spot.” Twenty to 25% of sinonasal carcinomas harbor high risk HPV. (3-7) In the sinonasal tract, HPV positivity is largely associated with the non-keratinizing squamous cell carcinoma phenotype, but Bishop, et al described a novel form of HPV-positive carcinoma characterized by areas that were highly reminiscent of solid adenoid cystic carcinoma and thus were originally designated as “HPV-related carcinoma with adenoid cystic-like features.”(8) In that original series of 8 cases, all cases: 1) arose from the sinonasal tract, 2) exhibited morphologic features of a salivary gland tumor including admixed ductal and myoepithelial elements, 3) displayed an unusual pattern of surface involvement where markedly atypical squamous cells colonized tracts of the sinonasal mucosa, and 4) failed to demonstrate the MYB gene fusions that characterize many true adenoid cystic carcinomas. (8) Since this sentinel publication, only one additional series (n=6) and a single-case report have been published.…”

Neuroendocrine Neoplasms of the Sinonasal Tract: Neuroendocrine Carcinomas and Olfactory Neuroblastoma

“…In a recent study of head and neck NEC, the 5-year survival of patients with SCNEC was 20.8 % [6]. The presence of human papillomavirus (HPV) has been described recently in rare examples of SC-NEC of the sinonasal tract [21,22]. The prevalence and clinical significance of HPV in SC-NEC is unclear and needs further study.…”

Elevated DNA methylation in malignant tumors of the sinonasal tract and its association with patient survival

“…Sinonasal carcinoma has been considered as a disease driven by progressive genetic alterations, such as mutations involving oncogenes or tumor suppressor genes, as well as chromosomal abnormalities 5 . In addition, approximately 20-30% of these tumors harbor transcriptionally active high risk human papillomavirus infection 7 . More recently, it has been demonstrated that sinonasal cancer is also driven by epigenetic alterations [8][9] .…”