What is the approach to diagnosis, management, and prognosis of pancreatic Neuroendocrine Tumors (NETs)?

Pancreatic Neuroendocrine Tumors: Diagnosis, Management, and Prognosis

Pancreatic neuroendocrine tumors (pNETs) require a systematic approach to diagnosis with histopathological confirmation, specific biochemical markers, and multimodal imaging, followed by treatment based on tumor grade, stage, and functionality status, with surgical resection as the only curative option for localized disease and various systemic therapies for advanced disease.

Epidemiology

• pNETs constitute approximately 30% of all gastroenteropancreatic neuroendocrine tumors (GEP-NETs) 1
• Incidence has steadily increased over recent decades to approximately 1.5-4.8 per 100,000 people 2, 3
• Classified as functional (40-55%) or non-functional (45-60%) based on hormone production and associated clinical syndromes 1

Clinical Presentation

Functional pNETs (40-55%)

Present with specific hormonal syndromes:

• Insulinoma: Hypoglycemia, confusion, diaphoresis
• Gastrinoma (Zollinger-Ellison syndrome): Peptic ulcers, diarrhea, abdominal pain
• Glucagonoma: Necrolytic migratory erythema, diabetes, weight loss
• VIPoma (Verner-Morrison syndrome): Watery diarrhea, hypokalemia, achlorhydria
• Somatostatinoma: Diabetes, gallstones, steatorrhea
• Other rare syndromes: ACTHoma, PTHrPoma, carcinoid syndrome 4

Non-functional pNETs (45-60%)

• Often asymptomatic until advanced
• May present with abdominal pain, weight loss, jaundice, or palpable mass
• Frequently discovered incidentally on imaging 1, 2

Diagnosis

Histopathology

• Confirmation by histopathology is essential
• WHO 2010 Classification based on Ki-67 proliferation index:
  • NET G1: Ki-67 ≤2%
  • NET G2: Ki-67 3-20%
  • NEC G3: Ki-67 >20% 1

Biochemical Markers

• Chromogranin A (CgA): Primary general biomarker for all pNETs (sensitivity 49-67%, specificity 77-78%) 5, 6
• Specific hormonal markers based on suspected syndrome:
  • Insulinoma: Fasting insulin, glucose, C-peptide
  • Gastrinoma: Fasting gastrin, gastric secretion studies
  • Glucagonoma: Fasting glucagon
  • VIPoma: Vasoactive intestinal peptide
  • Somatostatinoma: Somatostatin
  • Carcinoid syndrome: 24-hour urinary 5-HIAA 1, 5
• Neuron-specific enolase (NSE): Alternative marker when CgA is not elevated, especially in poorly differentiated tumors 1, 5

Imaging

• Conventional imaging:

  • Contrast-enhanced multiphase CT or MRI of abdomen/pelvis
  • Chest CT to assess for metastases 5

• Functional imaging:

  • Somatostatin receptor imaging (SRI): PET/CT using 68Ga-DOTA-TOC/-NOC/-TATE (preferred)
  • Octreoscan if PET/CT not available 1, 5

• Endoscopic procedures:

  • Endoscopic ultrasound (EUS) for pancreatic lesions
  • EUS-guided fine needle aspiration for tissue diagnosis 1

Management

Localized Disease

• Surgical resection is the only curative option:

  • Enucleation for small (<2 cm), well-circumscribed tumors away from pancreatic duct
  • Distal pancreatectomy for body/tail tumors
  • Pancreaticoduodenectomy (Whipple procedure) for head/uncinate process tumors 1, 3

• Small non-functional pNETs (<2 cm):

  • Active surveillance may be considered in selected cases
  • Decision should incorporate WHO grade and other prognostic markers 3

Advanced/Metastatic Disease

First-line Therapy

• Somatostatin analogs:
  • Lanreotide 120 mg SQ every 4 weeks for well-differentiated pNETs 7
  • Octreotide LAR 20-30 mg IM every 4 weeks 5
  • First-line therapy for all functional pNETs and control of hormonal syndromes 1

Targeted Therapies

• Everolimus: mTOR inhibitor approved for progressive pNETs 1, 5
• Sunitinib: Tyrosine kinase inhibitor, 37.5 mg daily without scheduled breaks
  • Demonstrated significant improvement in PFS (10.2 vs 5.4 months) compared to placebo 8

Cytotoxic Chemotherapy

• Temozolomide alone or in combination with capecitabine for progressive disease
  • Response rates up to 70% reported 1
• Streptozocin-based regimens (with doxorubicin and/or 5-FU) 1

Locoregional Therapies for Liver Metastases

• Transarterial chemoembolization (TACE)
• Transarterial radioembolization (TARE)
• Radiofrequency ablation (RFA) 5, 2

Peptide Receptor Radionuclide Therapy (PRRT)

• For somatostatin receptor-positive tumors that have progressed on other therapies 9

Management of Hormonal Syndromes

• Insulinoma: Diazoxide, frequent meals
• Gastrinoma: Proton pump inhibitors
• Glucagonoma: Amino acid infusions, zinc supplementation
• VIPoma: Fluid and electrolyte replacement
• Carcinoid syndrome: Somatostatin analogs 4

Follow-up and Monitoring

• Biochemical markers:

  • CgA every 3-6 months
  • Specific hormonal markers as appropriate 5

• Imaging:

  • CT or MRI every 3-6 months for NET G1/G2
  • Every 2-3 months for NEC G3 1

• Somatostatin receptor imaging:

  • Recommended after 18-24 months if somatostatin receptor 2a expression is confirmed 1

Prognosis

• 5-year survival rates:

  • Localized disease: 60-100%
  • Regional disease: 40%
  • Metastatic disease: 25-60% 1

• Prognostic factors:

  • WHO grade (Ki-67 index)
  • TNM stage
  • Functional status
  • Presence of distant metastases
  • Completeness of resection 1, 3

Special Considerations

• Carcinoid heart disease: Echocardiography recommended at diagnosis and during follow-up 5
• Carcinoid crisis: Prophylactic octreotide (100-200 μg IV bolus followed by continuous infusion of 50 μg/h) before procedures 5
• Steatorrhea and malabsorption: Evaluate for pancreatic exocrine insufficiency if symptoms develop 7

Emerging Approaches

• Biomarker development: Circulating tumor cells, microRNA profiles, and multiple transcript analysis 6
• Molecular characterization: ATRX/DAXX mutations, alternative lengthening of telomeres, and copy number variations as prognostic markers 3
• Novel therapeutic combinations: Anti-VEGF agents with immunotherapy 9