Pathophysiology and clinical syndrome: 1) Alpha-cell origin - glucagonomas arise from pancreatic islet alpha cells, autonomously secreting glucagon and proglucagon-derived peptides; tumors range from small (<2 cm) to large (>10 cm), commonly located in pancreatic body and tail; 2) Hyperglucagonemia effects - glucagon stimulates hepatic gluconeogenesis and glycogenolysis causing hyperglycemia/diabetes (75-95%); accelerates protein catabolism causing weight loss, hypoaminoacidemia, glossitis, cheilitis; promotes lipolysis; 3) Necrolytic migratory erythema (NME) - pathognomonic skin manifestation in 65-90%; erythematous, papulovesicular plaques on perioral, perineal, intertriginous areas, lower extremities; lesions evolve through erosion, crusting, hyperpigmentation; mechanism unclear, may relate to amino acid deficiency, zinc deficiency, essential fatty acid deficiency, glucagon-induced inflammatory cytokines; 4) Hypercoagulability - DVT and pulmonary embolism in 10-30%; mechanism includes glucagon-induced platelet aggregation, paraneoplastic effect, possibly elevated factor X; 5) Neuropsychiatric - depression, ataxia, cognitive impairment; 6) Other - normochromic normocytic anemia, hypoaminoacidemia, low zinc, GI symptoms (diarrhea, anorexia).
Diagnosis and localization: 1) Biochemical - fasting glucagon level (>500 pg/mL highly suggestive, >1000 diagnostic; mild elevations can occur in cirrhosis, renal failure, sepsis, fasting, prolonged exercise; differentiating MEN1 background); chromogranin A elevated; pancreatic polypeptide may co-elevate; insulin and C-peptide; HbA1c often elevated; CBC (anemia), albumin (low), zinc (low), amino acids (low); 2) Imaging - contrast-enhanced CT shows hypervascular pancreatic mass, often with liver metastases; MRI with hepatobiliary phase highly sensitive for liver metastases; endoscopic ultrasound for primary tumor characterization and FNA biopsy; 3) Functional imaging - 68Ga-DOTATATE PET/CT (somatostatin receptor scintigraphy) for staging - sensitivity >90% for detecting metastases, identifies receptor expression for therapy planning; 4) Histopathology - well-differentiated NET, chromogranin A and synaptophysin positive, glucagon staining confirms cell type; Ki-67 grade (G1 <3%, G2 3-20%, G3 >20%) determines prognosis and treatment; 5) MEN1 screening - 5-10% of glucagonomas occur in MEN1; screen with calcium, PTH, prolactin, MEN1 gene testing if family history.
Treatment and prognosis: 1) Surgical resection - definitive treatment when localized; distal pancreatectomy with splenectomy for tail tumors, central pancreatectomy or Whipple for body/head; cytoreductive (debulking) surgery in metastatic disease provides symptom relief and may improve survival; 2) Liver-directed therapy for metastases - liver resection if isolated, transarterial embolization (TAE) or chemoembolization (TACE), radiofrequency ablation, peptide receptor radionuclide therapy (177Lu-DOTATATE) for somatostatin receptor-positive disease; 3) Medical therapy - somatostatin analogs (octreotide LAR 20-30 mg monthly, lanreotide 120 mg monthly) reduce glucagon secretion and tumor growth, improve NME and other symptoms in 80-90%; 4) Targeted therapy - everolimus (mTOR inhibitor), sunitinib (TKI) for progressive metastatic disease; 5) Chemotherapy - capecitabine + temozolomide, streptozocin + 5-FU for high-grade or rapidly progressing tumors; 6) Supportive care - amino acid infusions and zinc supplementation rapidly improve NME (within days); insulin for diabetes; anticoagulation for thromboembolism; antidepressants; nutritional support; 7) Pre-operative preparation - 4-6 weeks of octreotide and amino acid supplementation reduces perioperative complications; preoperative anticoagulation assessment; 8) Prognosis - 5-year survival 75-85% if resectable, 50-60% if metastatic; somatostatin analog era has improved outcomes; multidisciplinary NET center management recommended.