Background: Therapeutic resources are often limited in rare tumors. NGS (Next Generation Sequencing) represents a valuable tool that can provide biological and prognostic information and guide therapeutic options. Here we describe a case series of the University Hospital of Verona, a center of excellence for neuroendocrine and pancreatic neoplasms. Methods: Between October 2020 and December 2022, 75 patients (pts) with a neuroendocrine neoplasm (NEN) or mixed neuroendocrine non-neuroendocrine neoplasia (MiNEN) underwent NGS analysis with an in-house assay CORE panel (covering 174 genes; 42 pts) or FoundationOne CDx panel (33 pts). We reported ACMG/AMP class IV-V molecular alterations as single nucleotide variations (SNVs), copy number variations (CNVs) including amplifications, deletions, fusions and loss of heterozygosity (LOH). Results: We included 53 well-differentiated neuroendocrine tumors (NETs), 17 poorly differentiated neuroendocrine carcinomas (NECs) and 5 MiNENs. The majority originated from gastro-entero-pancreatic tract (n=67, 89%). The most frequent gene alterations were TP53 (n=30; 12%: 28 SNV and 2 LOH); MEN1 (n=14, 5%: all SNV), CDKN2A (n=12; 5%: 2 SNV, 4 CNV LOH and 5 CNV loss), DAXX (n=12, 5%: all SNV) and RB1 (n=11, 4%: 8 SNV, 4 CNV LOH and 5 CNV loss). In MiNEN pts 3 druggable alterations were found: 1 TRIM-BRAF fusion, 1 SCL4A4-ROS1 fusion and 1 ERBB2 amplification. All MiNENs were MSS; median TMB (mTMB) was 4.86 mut/Mb. Among NET pts the most often altered genes were MEN1 (n=14), DAXX (n=12), TP53 (n=10), PTEN (n=7), CDKN2A (n=5), NF1 (n=5), TSC2 (n=5). The most prevalent mutations in NEC pts involved TP53 (n=17), RB1 (n=9), KRAS (n=7), CDKN2A (n=6), CDKN2B (n=5), CCNE1 (n=5), APC (n=4), SMAD4 (n=3). The mutational rate in NETs was 2.7 with a mTMB of 6.5; the mutational rate in NECs was 5.3 with a mTMB of 7.3 mut/Mb. In NET and NEC 23 actionable mutations were reported. In pancreatic NENs, DAXX mutation was present in 29% of NET G3 and absent in NEC cases. Among G1-G2 NET pts treated with PRRT in 2nd or further lines with a follow-up longer than 60 months (n=17), 6 (35%) were DAXX mutated and all (100%) were still alive at 5 years, compared to 7/11 (64%) in the DAXX wild type (wt) group. Focusing on NET with Ki67% between 3% and 55% (n=45), TP53 wt pts (n=35, 78%) showed a better median overall survival (mOS) than TP53 mutated (n=10, 22%) pts (131.3 vs 56.7 months; p= 0.0433). Conclusions: Our data support the role of NGS in pancreatic rare histologies. This work highlighted the negative prognostic role of TP53 status in G2-G3 NETs, the potential predictive role of DAXX in G1-G2 NET treated with PRRT and its contribution to the differential diagnosis between NET and NEC. Our findings suggest that the pathogenesis in NET is mostly mediated by defects in tumor suppressor genes, while the role of oncogene alterations seem to acquire more importance with increasingly poor differentiation.