Pancreatic Neuroendocrine Tumors - NET

Diagnostic Algorithm

Clinical Background

Pancreatic neuroendocrine tumors (PNET) are rare tumors of pancreatic neuroendocrine cells that may be functional or nonfunctional.

Epidemiology

• Incidence – 1-1.5/100,000
• Age – onset 40s-50s
• Sex – M:F, equal
• Occurrence – usually sporadic

Risk Factors

• Genetic – May be associated with multiple endocrine neoplasia type 1 (MEN 1), von Hippel-Lindau syndrome, and type 1 (peripheral) neurofibromatosis

Pathophysiology

• Solid or cystic tumors located anywhere within the pancreas
• Tumors may be functional or non-functional
  • Functional tumors secrete hormones to produce classic clinical syndrome (eg, Verner-Morrison syndrome associated with vasoactive intestinal polypeptide [VIP] secretion)
  • Non-functional tumors may secrete hormones but do not cause symptoms
• Frequency of occurrence – non-functional >insulinoma >gastrinoma >glucagonoma >VIPoma >somatostatinoma
• Molecular pathogenesis of pancreatic NETs is incompletely understood
  • Loss of heterozygosity at 11q13 and MEN1 mutations have been identified in sporadic NETs

Clinical Presentation

• Tumor increasingly identified incidentally by imaging
• Patients may present with one of five common hormonal syndromes
  • Insulinoma
  • Zollinger-Ellison syndrome
  • Glucagonoma
  • Verner-Morrison syndrome
  • Somatostatinoma syndrome

Treatment

• Relief of symptoms caused by hormone secretion
• Surgical resection
• Somatostatin analogues

Diagnosis

• Indications for testing – pancreatic mass; presentation of one of the five functional syndromes associated with the tumor
• Laboratory testing
  • Elevated levels of insulin, C-peptide, gastrin, glucagon, VIP, or somatostatin
  • Chromogranin A (sensitivity 60-100% in metastatic disease, 50% in early disease)
• Histology
  • Nested or trabecular arrangement of small- to medium-sized cells
    • Finely granular eosinophilic cytoplasm
    • Central, round to oval nuclei
    • Stippled chromatin (“salt and pepper”)
  • Immunohistochemistry – chromogranin and synaptophysis
    • May also stain for commonly secreted hormones
      • Positive staining is not always associated with clinical syndrome
      • Not sufficient as diagnosis without clinical syndrome
• Imaging Studies
  • CT
  • MRI
  • Somatostatin-receptor scintigraphy (not useful in insulinomas)

Prognosis

• Malignancy determined by tumor cell invasion of surrounding structures
  • Duodenum, bile duct, lymph nodes, or peripancreatic fat may be involved
  • Each pancreatic NET variant has a different risk of malignant behavior
• Tumors may be categorized according to WHO or TNM classification
• Survival rate is excellent for patients with complete resections (90-100%), but is lower for those with metastatic disease (25-50%)

Differential Diagnosis

• Solid-pseudopapillary tumor
• Acinar cell carcinoma
• Pancreatoblastoma
• Paraganglioma
• Pancreatic ductal adenocarcinoma
• Chronic pancreatitis

Pharmacogenetics and Therapeutic Drug Monitoring

Screening

Monitoring

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

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Test Name and Number	Comments
Pancreatic Polypeptide 0099436 Method: Radioimmunoassay

General References