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Simple Summary: Poorly differentiated sinonasal carcinomas (PDSNCs) are rare neoplasms that include a wide spectrum of malignancies characterized by alteration in different epigenetic mechanisms (SWI/SNF complex, IDH2, NUT). The aim of our study was to verify if the identification of specific genetic and epigenetic alterations can be useful to recognize different clinico-pathological subsets of PDSNCs to guide treatment decisions. In our cohort, 14 cases showed alterations in SWI/SNF complex or IDH2 genes, which were associated with a higher global DNA methylation level and worst prognosis. The integration of genetic and epigenetic features appears to be a good strategy to improve the clinico-pathological classification of these tumors and to recognize distinct prognostic entities that deserve tailored clinical management. Background: Poorly differentiated sinonasal carcinomas (PDSNCs) are rare and aggressive malignancies, which include squamous cell carcinoma (SCC), sinonasal undifferentiated carcinoma (SNUC), and neuroendocrine carcinomas (NEC). Several epigenetic markers have been suggested to support the histopathological classification, predict prognosis, and guide therapeutic decision. Indeed, molecularly distinct subtypes of sinonasal carcinomas, including SMARCB1-INI1 or SMARCA4 deficient sinonasal carcinoma, isocitrate dehydrogenase (IDH)-mutant SNUC, ARID1A mutant PDSNCs, and NUT carcinomas, have recently been proposed as separate entities. Identification of aberrant DNA methylation levels associated with these specific epigenetic driver genes could be useful for prognostic and therapeutic purpose. Methods: Histopathological review and immunohistochemical study was performed on 53 PDSNCs. Molecular analysis included mutational profile by NGS, Sanger sequencing, and MLPA analyses, and global DNA methylation profile using LINE-1 bisulfite-PCR and pyrosequencing analysis. Results: Nine SWI/SNF complex defective cases and five IDH2 p.Arg172x cases were identified. A significant correlation between INI-1 or IDH2 defects and LINE-1 hypermethylation was observed (p = 0.002 and p = 0.032, respectively), which were associated with a worse prognosis (p = 0.007). Conclusions: Genetic and epigenetic characterization of PDSNCs should be performed to identify distinct prognostic entities, which deserved a tailored clinical treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: The gene expression profile of ONB defines a group of patients with a dismal prognosis and identifies potentially targetable pathways. Better prognostic stratification may offer new tailored approaches for the treatment and follow-up of ONB. The integration of new therapeutic agents with standard surgical and RT strategies may improve the outcomes in cases with worse prognoses. Furthermore, the ontogenesis of ONB in basal and neural subtypes is mirrored by different transcriptional pathways, paving the way towards different therapeutic approaches. Olfactory neuroblastoma (ONB) is a rare sinonasal neoplasm with a peculiar behavior, for which limited prognostic factors are available. Herein, we investigate the transcriptional pathways altered in ONB and correlate them with pathological features and clinical outcomes. We analyze 32 ONB patients treated with curative intent at two independent institutions from 2001 to 2019 for whom there is available pathologic and clinical data. We perform gene expression profiling on primary ONB samples and carry out functional enrichment analysis to investigate the key pathways associated with disease-free survival (DFS). The median age is 53.5 years; all patients undergo surgery and a pure endoscopic approach is adopted in the majority of cases (81.2%). Most patients have advanced disease (stages III–IV, 81.2%) and 84.4% undergo adjuvant (chemo)radiotherapy. The median follow-up is 35 months; 11 (26.8%) patients relapse. Clinical characteristics (gender, stage and Hyams' grade) are not associated with the outcomes. In contrast, TGF-beta binding, EMT, IFN-alpha response, angiogenesis, IL2-STAT5 and IL6-JAK-STAT3 signaling pathways are enriched in patients experiencing recurrence, and significantly associated with shorter DFS. Clustering of transcriptional profiles according to pathological features indicates two distinct molecular groups, defined by either cytokeratin-positive or -negative immunostaining. Definition of the characterizing ONB transcriptomic pathways may pave the way towards tailored treatment approaches. [ABSTRACT FROM AUTHOR]