A subset of sinonasal undifferentiated carcinoma is associated with transcriptionally active high-risk human papillomavirus by in situ hybridization: a clinical and pathologic analysis

Sinonasal undifferentiated carcinoma (SNUC) is an aggressive malignancy with a poor prognosis, and pathologically, it is a diagnosis of exclusion. Rendering this diagnosis can be challenging in practice because of the large number of diverse entities in the differential diagnosis. We encountered an index case of a sinonasal carcinoma otherwise diagnosable as SNUC which, on further investigation, demonstrated strong and diffuse P16 expression, as well as diffuse expression of high-risk human papillomavirus (hrHPV) RNA by in situ hybridization (ISH). We therefore hypothesized that a subset of cases previously diagnosed as SNUC may in fact harbor transcriptionally active hrHPV. We further investigated a cohort of 25 SNUC cases in our pathology archives and performed ISH for hrHPV RNA on cases that demonstrated >70% nuclear and cytoplasmic P16 expression, criteria which, in other anatomic sites, correlates strongly with the presence of hrHPV. Twelve of 25 SNUC cases were P16 positive, and of these, 5 were positive for hrHPV by ISH. Thus, 20% of all SNUC cases in this cohort harbored transcriptionally active hrHPV. Herein, we report a clinical and pathologic analysis of these cases, including differential diagnostic considerations and comparison of their clinical behavior with SNUC cases that are negative for hrHPV by ISH.