A large number of tumor types arise from the mucosa of the sinonasal cavities. Although presenting clinically distinct behavior, due to poorly differentiated histologic features, they can be difficult to classify correctly. Our aim was to investigate whether IDH2 and IDH1 mutations may be specific to a subset of undifferentiated and poorly differentiated sinonasal carcinomas. A total of 125 tumor samples of 7 different histologic subtypes were analyzed for IDH mutations by sequencing and mutant-specific immunohistochemistry, and the results were correlated to clinical and follow-up data. The highest incidence of IDH2 mutations occurred in sinonasal undifferentiated carcinoma, with 11/36 (31%) cases affected. However, also, 1/9 neuroendocrine carcinomas, 2/4 high-grade non–intestinal-type adenocarcinomas, and 1/8 poorly differentiated squamous cell carcinomas carried the IDH2 mutation, whereas 1/48 intestinal-type adenocarcinomas harbored an IDH1 mutation. Immunohistochemical analysis of mutant IDH1/2 produced a number of false-negative results, but also 1 false-positive tumor was found. Disease-specific survival was more favorable in IDH2-mutant versus wild-type cases. Our data suggest that IDH-mutant sinonasal cancers, independent of their histologic subtype, may represent a distinct tumor entity with less aggressive clinical behavior. Clinically, patients with these mutations may benefit from specific IDH-guided therapies.

The PI3K/AKT/mTOR signaling pathway has emerged as one of the most frequently deregulated in head and neck squamous cell carcinomas (HNSCC). Numerous alterations of various upstream and downstream components have been described; however, their prognostic significance and impact on HNSCC patient survival remains to be established. This was addressed using an unbiased cohort of 93 consecutive and homogeneous surgically treated HNSCC patients and results confirmed in 432 HNSCC patients. Our findings reveal the high prevalence of S6 phosphorylation, a surrogate marker of mTORC1 activation, in HNSCC specimens (>70%) and, more importantly, demonstrate its relevance on clinical outcome. Phosphorylation of ribosomal protein S6 on either Ser235/236 or Ser240/244 was consistently and significantly correlated with favorable prognosis, although with differences depending on the tumor site. Thus, p-S6 expression was significantly correlated with better disease-specific survival specifically in the subgroup of laryngeal carcinoma patients (P< 0.001). In addition, multivariate regression models revealed p-S6 to be an inverse and independent predictor of lymph-node metastasis (P= 0.004) and distant metastasis (P= 0.006). Taken together, this study unveils an unprecedented correlation of mTOR activation with improved clinical outcome in patients with laryngeal carcinomas and uncovers the potential of p-S6 expression as a good prognostic biomarker and an inverse predictor of lymph node and distant metastases. These results should be of broad interest as immunohistochemical detection of p-S6 may help to stratify patients and guide treatment decisions.

Background: To evaluate the involvement of EGFR signalling and HPV infection in a cohort of inverted sinonasal papilloma (ISP) and sinonasal squamous cell carcinoma (SNSCC) and their value for prognosis and clinical treatment. Methods:We analysed 55 ISP, 14 SNSCC associated with ISP (SNSCC-isp) and and 60 SNSCC not associated with ISP (SNSCC-novo) for EGFR gene mutation and copy number gain, protein expression of EGFR and phosporylated EGFR (pEGFR), and HPV-infection and KRAS mutation. Findings were correlated to clinico-pathological and follow-up data. Results:We found EGFR exon 20 mutations in 38% (7/18) ISP, in 50% (6/12) SNSCC-isp and in 5% (1/19) SNSCC-novo. EGFR was expressed in 92% of ISP, while pEGFR was observed in 54% (21/39). SNSCC-isp and SNSCC-novo demonstrated comparable expression of EGFR (57% and 33%) and of pEGFR (44% and 38%). We observed an inverse relation between EGFR exon 20 mutation and pEGFR expression. Four of 39 (10%) ISP carried HPV-16. Oncogenic HPV was detected in 3/12 (25%) SNSSC-isp and in 1/8 (13%) SNSCC-novo. KRAS mutations were not detected in any of the samples. HPV infection was inversely correlated with pEGFR expression but not with EGFR mutation. ISP with EGFR activation by mutation or by phosphorylation had longer ISP-free survival, however, neither EGFR exon 20 mutation, pEGFR expression nor HPV infection demonstrated prognostic value in SNSCC.Conclusions: EGFR exon 20 mutation is frequent in ISP and SNSCC-isp, while activation of EGFR through phosphorylation also plays an important role. Our data indicate that a large proportion of SNSCC patients could benefit from therapy with modern EGFR inhibitors.

Background. Intestinal-type adenocarcinoma (ITAC) is a rare tumour occurring in the ethmoid sinus. Recent years have brought advances in endoscopic surgery and precision radiotherapy; however, five-year overall survival has not improved and remains at 35–80%, depending on tumour stage and histology. Therefore, there is a need for new therapeutic options. Methods. We evaluated CD8+ tumour-infiltrating lymphocytes (TILs) and tumour microenvironment immune type (TMIT, combining CD8+ TILs and PD-L1) as predictive biomarkers for immunotherapy in a series of 133 ITAC. All results were correlated to clinical and follow-up data. Results. The presence of intratumoural CD8+ TILs was low in 57% of cases and high in 8% of cases. Tumoural PD-L1 positivity was observed in 26% of cases. CD8+ TILs and TMIT correlated with the histological subtype of ITAC and with better overall survival. The presence of stromal PD-L1-positive macrophages was related to intratumoural CD8+ TILs. PD-L1 expression on tumour cells or macrophages did not show prognostic value. Conclusions. TMIT classification did not have additional prognostic value over CD8+ TILs alone. The modest percentage of CD8high/PD-L1pos cases indicates that ITAC is a lowly immunogenic tumour type. Nevertheless, a proportion of ITAC, especially the papillary and colonic subtypes, could benefit from therapy with immune checkpoint inhibitors.