What is the management approach for pancreatic neuroendocrine tumors (PNETs) in multiple endocrine neoplasia type 1 (MEN1) syndrome?

Management of Pancreatic Neuroendocrine Tumors (PNETs) in MEN1 Syndrome

For patients with MEN1 syndrome, surgical resection is recommended for nonfunctioning PNETs ≥2 cm in size to prevent metastatic disease, while tumors <2 cm can be safely managed with watchful waiting. 1, 2

Diagnostic Evaluation

Initial Biochemical Assessment

• Mandatory baseline tests:
  • Chromogranin A (CgA)
  • 5-hydroxyindoleacetic acid (5-HIAA) in 24-hour urine 3, 1
• Additional tests based on clinical suspicion:
  • Thyroid function tests
  • PTH and calcium levels
  • Calcitonin
  • Prolactin
  • Alpha-fetoprotein
  • Carcinoembryonic antigen (CEA)
  • β-human chorionic gonadotrophin (β-HCG) 3, 1
• Specific hormone tests for suspected functional syndromes:
  • Insulinoma: insulin, C-peptide, glucose levels
  • Gastrinoma: gastrin levels
  • Glucagonoma: glucagon, blood glucose
  • VIPoma: VIP levels, electrolytes 1

Imaging Studies

• Multimodality approach is recommended 3:
  • CT or MRI for detecting primary tumor and metastases
  • Somatostatin receptor scintigraphy (SSRS) or preferably Gallium-68 PET/CT (most sensitive)
  • Endoscopic ultrasound (EUS) - particularly valuable for small pancreatic lesions
  • Endoscopy for gastric, duodenal, and pancreatic tumors
  • Digital subtraction angiography (DSA) and venous sampling as complementary studies 3, 1

Management Approach for PNETs in MEN1

Nonfunctioning PNETs (NF-PNETs)

• For NF-PNETs <2 cm:

  • Watchful waiting is recommended 1, 2
  • Regular surveillance with imaging every 6-12 months
  • This approach avoids major surgery without compromising oncological safety 2

• For NF-PNETs 2-3 cm:

  • Surgical resection should be considered 1, 4
  • Decision should factor in tumor growth rate and location

• For NF-PNETs >3 cm:

  • Surgical resection strongly recommended due to high risk of metastatic disease 1, 2
  • Watchful waiting is not advisable as 5 out of 6 patients managed conservatively developed liver metastases or died 2

Functional PNETs

• Insulinomas:

  • Resection regardless of size due to metabolic complications 3
  • For MEN1 insulinoma: distal pancreatectomy with enucleation of tumors from the head of the pancreas 3
  • Control hypoglycemia preoperatively with diet and/or diazoxide 1

• Gastrinomas:

  • Resection of tumors >2-2.5 cm to decrease risk of metastatic disease 3
  • Duodenotomy, excision of multiple tumors, and lymph node resection 3
  • For pancreatic head gastrinomas: enucleation or Whipple procedure 3
  • Preoperative control with proton pump inhibitors 1

Surgical Approaches

• Peripheral tumors and small (<2 cm) nonfunctional tumors:

  • Open or laparoscopic enucleation/local resection
  • Spleen-preserving distal pancreatectomy 3

• Larger (>2 cm) or malignant-appearing tumors:

  • Total removal with negative margins
  • Regional lymph node resection
  • Tumors in head: pancreatoduodenectomy (Whipple)
  • Tumors in body/tail: distal pancreatectomy with or without splenectomy 3

Preoperative Management

• Control hormone-related symptoms before surgery 1
• Consider cholecystectomy during abdominal surgery if long-term somatostatin analog therapy is anticipated 3
• Administer octreotide therapy parenterally before anesthesia induction for functional tumors to prevent carcinoid crisis 3

Follow-up and Surveillance

• Regular follow-up every 3-6 months for more than 5 years after curative surgery 1
• Biochemical markers and imaging (CT or MRI) every 6 months during treatment 1
• Active surveillance program for early detection of MEN1-associated disease 5

Special Considerations

• PNETs are the most common cause of death in MEN1 patients 5, 6
• Multi-focal disease is common in MEN1, unlike sporadic PNETs 6
• Current research focuses on identifying biomarkers to better predict tumor behavior and developing medical therapies that may delay or prevent pancreatic surgery 7, 4

Treatment for Advanced Disease

• Somatostatin analogs for symptom control and tumor stabilization 1
• Everolimus for progressive, well-differentiated pancreatic NETs 1
• Chemotherapy for inoperable or metastatic disease 1
• Liver-directed therapies for hepatic metastases 5