P-NENs are classified as functional (F-) or non-functional (NF-) depending on the presence or absence of a clinical hormonal hypersecretion syndrome. Moreover, the WHO 2017 classification of pNENs distinguishes between well-differentiated pancreatic neuroendocrine tumors (pNETs) and poorly differentiated pancreatic neuroendocrine carcinomas (pNECs). pNETs are then divided according to a grading scheme based on Ki67 index in pNETs-G1 (Ki67 index ≤3%) and pNETs-G2 (Ki67 index between 4% and 20%). pNECs are all G3, with a Ki67 index >20%. Endoscopic ultrasound with fine-needle biopsy (EUS-FNB) demonstrated safe and effective preoperative grading based on the Ki-67 proliferative index. However, downstaging rate is not neglectable, reaching 15% in a recent metanalysis. Moreover, recent whole-exome and whole genome sequencing studies revealed that the mutually exclusive inactivating mutations in death domain-associated protein (DAXX) and/or in α-thalassemia/mental retardation X-linked (ATRX) chromatin remodeling genes are associated with more aggressive disease. In a retrospective study, the investigators recently evaluated the correspondence of DAXX/ATRX expression on 41 EUS-FNB samples with corresponding surgical specimens demonstrating a 95.1% (almost perfect agreement, κ = 0.828; p < 0.001) and 92.7% (substantial agreement, κ = 0.626; p < 0.001) concordance for DAXX and ATRX expression, respectively. This study aims to evaluate the potential clinical/prognostic role of DAXX/ATRX expression as implementation of the currently used Ki67-based grading, evaluated on EUS-FNB samples in a prospective cohort of patients with NF-pNETs

Inclusion Criteria:

• Age ≥18 years
• Cyto/histologic diagnosis of pNETs
• Signed informed consent

Exclusion Criteria:

• Functional pNETs
• Multiple pancreatic nodules
• Diagnosis of MEN-1 or Von-Hippel Lindau
• Mixed types (e.g., mixed neuroendocrine-acinar/adenocarcinoma) or neuroendocrine carcinomas
• Predominantly cystic lesions (more than 50% of the volume).
• Metastatic tumors at the time of diagnosis
• Known bleeding disorder that cannot be sufficiently corrected with co-fact or fresh frozen plasma
• Use of anticoagulants that cannot be discontinued
• INR >1.5 or platelet count <50.000
• Pregnancy or breastfeeding
• Failure to sign the patient's or closest relative's informed consent

Patients with a diagnosis of pancreatic neuroendocrine tumors