Clinicopathological and genomic features in patients with head and neck neuroendocrine carcinoma

Abstract

Neuroendocrine carcinoma (NEC) of the head and neck is a rare type of malignancy, accounting for only 0.3% of all head and neck cancers, and its clinicopathological and genomic features have not been fully characterized. We conducted a retrospective analysis of 27 patients with poorly differentiated NEC of the head and neck seen at our institution over a period of 15 years. Patient characteristics, adopted therapies, and clinical outcomes were reviewed based on the medical records. Pathological analysis and targeted sequencing of 523 cancer-related genes were performed using evaluable biopsied/resected specimens based on the clinical data. The most common tumor locations were the paranasal sinus (33%) and the oropharynx (19%). Eighty-one percent of the patients had locally advanced disease. The 3-year overall survival rates in all patients and in the 17 patients with locally advanced disease who received multimodal curative treatments were 39% and 53%, respectively. Histologically, large cell neuroendocrine carcinoma was the predominant subtype (58% of evaluable cases), and the Ki-67 labeling index ranged from 59 to 99% (median: 85%). Next-generation sequencing in 14 patients identified pathogenic/likely pathogenic variants in TP53, RB1, PIK3CA-related genes (PREX2, PIK3CA, and PTEN), NOTCH1, and SMARCA4 in six (43%), three (21%), two (14%), two (14%), and one (7%) patients, respectively. Sequencing also detected the FGFR3-TACC3 fusion gene in one patient. The median value of the total mutational burden (TMB) was 7.1/Mb, and three patients had TMB ≥ 10. Regardless of the aggressive pathological features, our data revealed favorable clinical characteristics in the patients with locally advanced disease who received curative treatment. The lower TP53 and RB1 mutation prevalence rates compared to those described for small cell lung cancer suggests the biological heterogeneity of NEC in different parts of the body. Furthermore, the FGFR3-TACC3 fusion gene and mutations in genes encoding the components of the NOTCH and PI3K/AKT/mTOR pathways found in our study may be promising targets for NEC of the head and neck.

Genomic characterization reveals distinct mutation landscapes and therapeutic implications in neuroendocrine carcinomas of the gastrointestinal tract

“…However, GI‐SCNECs had a significantly lower frequency of RB1 mutations than SCLCs. Concordantly, RB1 mutation frequencies varied considerably across different anatomic locations according to previous studies [ 4 , 33 , 34 ]. Moreover, multiple other genes, including those detected in GI adenocarcinomas (e.g., APC and CTNNB1 ), were also differentially mutated between GI‐NECs and their lung counterparts.…”

Identification of functional pathways and molecular signatures in neuroendocrine neoplasms by multi-omics analysis

“…In detail, the method allows the simultaneous analysis of multiple biomarkers from different tumor tissues, assessing multiple variant types in a single assay, including small nucleotide variants (SNVs), indels, splice variants and emerging immunotherapy biomarkers such as tumor mutational burden (TMB) and microsatellite instability (MSI). This method has also been recently applied successfully for the identification of genomic features of head and neck neuroendocrine carcinoma [ 49 ]. In our case, all the sequence variants identified have been reported in Additional file 2 : Table S2.…”

Morphologic and Molecular Heterogeneity of Cervical Neuroendocrine Neoplasia

“…In the lung, most harbor concurrent TP53 and RB1 mutations42 also frequent in gastrointestinal and pancreatic SCNECs 31,43,44. Several studies have analyzed the molecular features of cervical SCNECs22–25 reporting recurrent alterations in PI3K/AKT/mTOR (most frequently PIK3CA and PTEN ), RAS/MAPK pathways (most frequently KRAS ), as well as MYC and less frequently in TP53 and rarely in RB1 , a mutational profile closer to that reported in common cervical carcinomas8 and other HPV-associated malignancies including head and neck NECs 45–48. In addition, while mutations in pulmonary SCNECs have been shown to have a tobacco-related signature,42,49,50 cervical SCNECs have aging-related and APOBEC signatures,25,26 akin to the molecular signatures of HPV-associated tumors including cervical and head and neck carcinomas 8,26,51–53.…”