Sampling performance of EUS-Guided fine-needle biopsy in pancreatic neuroendocrine tumors: A systematic review and meta-analysis.

Per NCCN Neuroendocrine and Adrenal Tumors v2.2025: Work up a suspected pancreatic NET with multiphasic pancreatic-protocol contrast CT and/or MRI; consider EUS with biopsy (FNB) for tissue; use somatostatin-receptor imaging with 68Ga- or 64Cu-DOTATATE PET/CT when it will change management. Obtain biochemical/hormonal evaluation only when a functional syndrome is clinically suspected (not routine for nonfunctioning tumors). Grade by mitotic count and Ki-67 under the WHO classification of neuroendocrine neoplasms (G1 <3%, G2 3-20%, G3 >20%). Consider genetics referral/germline testing for inherited syndromes, principally MEN1 and VHL (less commonly NF1, TSC). LOCALIZED well-differentiated G1/G2: for an incidentally found sporadic nonfunctioning tumor <=2 cm without high-risk features, that is, none of the worrisome imaging/pathologic features that favor resection: main pancreatic-duct dilation (>3 mm) or biliary-duct obstruction, pathologic regional lymphadenopathy on cross-sectional imaging, or vascular encasement/invasion of adjacent structures (grade, functional/symptomatic status, size >2 cm, and interval growth are addressed separately below), NCCN lists BOTH observation and surgery as options; observed lesions are followed with multiphasic CT/MRI (± SSTR-PET as indicated) at 3-12 months, then every 6-12 months if stable. For tumors >2 cm, functional/symptomatic, higher-grade, or enlarging on surveillance, surgical resection (enucleation, distal pancreatectomy, or pancreaticoduodenectomy by location) is recommended and can be curative. ADVANCED/METASTATIC well-differentiated: somatostatin analogs (octreotide LAR or lanreotide) are a preferred first-line option for SSTR-positive, lower-grade/lower-proliferation tumors. 177Lu-DOTATATE PRRT is now also a first-line option for SSTR-positive disease on the strength of NETTER-2, whose population was newly diagnosed grade 2/3 GEP-NET with Ki-67 10-55% (median PFS 22.8 vs 8.5 months), keep the Ki-67 10-55% window and SSTR-positivity as the qualifiers, not an open-ended 'Ki-67 >=10%.' Subsequent-line options for progressive disease include everolimus, sunitinib (pancreatic primary), CAPTEM (capecitabine + temozolomide), PRRT if not already used, and cabozantinib, FDA-approved March 26, 2025 and included by NCCN as a category 1 option for previously treated, unresectable/locally advanced/metastatic well-differentiated pancreatic NET (the FDA label specifies only 'previously treated,' without a required prior-drug sequence).