Methylation Drivers and Prognostic Implications in Sinonasal Poorly Differentiated Carcinomas.

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.

Exploring the role of nasal cytology in chronic rhinosinusitis.

OBJECTIVE: Characterising the eosinophilic profile represents the main step in chronic rhinosinusitis (CRS) endotyping. The aim of the study is to verify the correlation between different methods for tissue eosinophilia quantification. METHODS: 33 CRS patients undergoing endoscopic sinus surgery and 30 controls undergoing non-CRS surgeries were enrolled. Blood venous sampling, nasal biopsy on uncinate process (UP), nasal cytology on inferior turbinate (IT) and middle meatus (MM) were performed. RESULTS: Differences in eosinophil count in blood (P=0.0001), UP (P#x003C;0.0001), IT (P = 0.01) and MM (P = 0.0006) were significant between CRS cases and controls. A weak correlation was found between UP and blood eosinophil count (r = 0.34, P = 0.006) and between UP and IT eosinophil count (r = 0.30, P = 0.017). Moderate correlation between UP and MM (r = 0.51, P #x003C; 0.0001) was shown. ROC analysis predicted eosinophilic CRS with an overall low sensitivity. Once allergic patients were excluded from the analysis, the sensitivity decreased for sampling on IT and increased for MM sampling. CONCLUSIONS: This study suggests that MM cytology gives more accurate information on the degree of tissue eosinophilia. Replication in wide and unbiased cohorts is necessary to verify these results and define accurate thresholds.

Endoscopic Endonasal Resection of Sinonasal and Nasopharyngeal Pleomorphic Adenomas: A Case Series.

The aim of this study is to describe the clinicopathological characteristics of intranasal pleomorphic adenomas (PAs), as well as the role and outcomes of endoscopic endonasal resection. A retrospective review of the clinical data from patients with PA of the nasal cavity who were treated by the authors at three tertiary medical centers between June 1998 and December 2019. A total of five patients with PA were found. Three patients were male, two were female and their mean age was 62.2 years. All cases were resected "en bloc" with endoscopic endonasal approach. No evidence of disease was observed during a mean follow-up of 10.6 years. No case presented with malignant transformation into carcinoma ex-PA. PA of the sinonasal tract and the nasopharynx is difficult to diagnose due to nonspecific clinical and radiological findings. Endoscopic endonasal approaches can be considered the gold standard in the treatment of these tumors and provide excellent visual control of the surgical field and clear margins.

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.

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 ISP-associated 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.

Endoscopic endonasal resection of adenoid cystic carcinoma of the sinonasal tract and skull base.

OBJECTIVES: Adenoid cystic carcinoma (ACC) is a locally aggressive salivary gland malignancy prone to perineural invasion and local recurrences. In the literature, few data exist to guide treatment when this tumor involves the paranasal sinuses and skull base. We report our experience in the management of sinonasal adenoid cystic carcinoma through an endoscopic endonasal approach. METHODS: Retrospective analysis of patients affected by sinonasal ACC treated through an endoscopic endonasal approach from 1997 to 2015, managed at the Universities of Varese and Brescia, Italy. RESULTS: Thirty-four patients were included in the analysis. The ethmoid sinus (55.9%), nasal septum (17.7%), maxillary sinus (11.7%), and sphenoid sinus (5.9%) were the primary tumor sites encountered. Twenty patients (58.8%) presented with T3 or T4, without any systemic spreading. Twenty-nine patients underwent endoscopic transnasal resection, whereas the involvement of the anterior skull base in five cases required a transnasal endoscopic craniectomy. Overall, 20 of 34 (58.8%) patients received some form of adjuvant radiotherapy. The follow-up ranged from 12 to 202 months (mean of 73.2 months). The 5-year overall, disease-specific, and recurrence-free survival rates were 86.5% ± 7.39%, 86.5% ± 7.39%, and 71.8% ± 8.67%, respectively. CONCLUSIONS: The endoscopic approach is safe and effective for selected sinonasal ACC, reducing the comorbidities of the external approaches while producing similar oncological results. High T-stage, grade III histology, positive surgical margins, and perineural infiltration all have an important negative prognostic value. LEVEL OF EVIDENCE: 4 Laryngoscope, 129:1071-1077, 2019.

Primary Ectopic Ethmoidal Craniopharyngioma.

Craniopharyngiomas are benign but aggressive epithelial tumors usually originating in the anterior lobe of the pituitary gland from squamous remnants of an incompletely involuted craniopharingeal duct developing from the Rathke pouch. To the authors' knowledge only 1 patient of a primary isolated ethmoidal craniopharyngioma has been reported in the literature.The authors report the case of a 17-year-old boy with a primary extracranial ethmoidal craniopharyngioma. An endoscopic endonasal approach was employed to resect the tumor. After 2 years of clinical and radiological follow-up no recurrence of disease was observed.Primary ethmoidal craniopharyngiomas are rare entities and biopsy is necessary for diagnosis. However, a preoperative assessment by means of nasal endoscopy, computed tomography scan, and enhanced magnetic resonance imaging is mandatory to better evaluate the extension and characteristics of the tumor. The endoscopic endonasal technique is a safe and effective approach for the treatment of these lesions.