Clinical meaning
Pancreatic neuroendocrine tumors (PanNETs) originate from the islets of Langerhans — clusters of endocrine cells within the pancreas that include beta cells (insulin), alpha cells (glucagon), delta cells (somatostatin), PP cells (pancreatic polypeptide), and enterochromaffin-like cells. PanNETs are classified as functional (producing hormonal syndromes) or non-functional (hormonally silent, comprising 60-90% of cases). Functional tumors are named by the hormone they hypersecrete: insulinomas (most common functional PanNET) autonomously secrete insulin independent of blood glucose, causing recurrent fasting hypoglycemia with Whipple triad (symptoms + documented low glucose + resolution with glucose administration); gastrinomas cause Zollinger-Ellison syndrome through massive gastric acid hypersecretion leading to refractory peptic ulcers; glucagonomas produce a distinctive syndrome of necrolytic migratory erythema, new-onset diabetes, weight loss, and DVT; VIPomas cause profuse secretory diarrhea with hypokalemia and achlorhydria (WDHA/Verner-Morrison syndrome). WHO grading is based on proliferative index: G1 (Ki-67 <3%) are well-differentiated with indolent behavior, G2 (Ki-67 3-20%) are intermediate grade, and G3 (Ki-67 >20%) are high-grade neuroendocrine carcinomas with aggressive behavior. All PanNET cells express somatostatin receptors (especially SSTR2), which is exploited diagnostically with 68Ga-DOTATATE PET/CT imaging and therapeutically with somatostatin analogs (octreotide, lanreotide) that suppress hormone secretion and exert antiproliferative effects through cell cycle arrest. The MEN1 syndrome (autosomal dominant, menin gene mutation on chromosome 11q13) is the most important hereditary predisposition, causing multifocal PanNETs alongside primary hyperparathyroidism and pituitary adenomas.