Pancreatic Neuroendocrine Tumors - NET

Diagnosis

Indications for Testing

• Pancreatic mass; presentation of a functional syndrome associated with pancreatic neuroendocrine tumors (PNET)
  • Most PNETs are nonfunctional

Laboratory Testing

• Lab testing based on specific syndrome presentation
  • Insulinoma – glucose, insulin, proinsulin, c-peptide
  • Zollinger-Ellison syndrome – gastrin, electrolytes
    • Patient should be off acid-suppressive medication for at least 7-10 days prior to testing
  • Glucagonoma – glucagon (concentration generally >fivefold over the reference range)
  • VIPoma – vasoactive intestinal polypeptide (VIP), electrolytes
  • Somatostatinoma – somatostatin (circulating somatostatin concentrations often >100-fold over the reference range)
  • Multiple endocrine neoplasia type 1 (MEN1) – consider family history of patient to determine MEN1 involvement
• Chromogranin A (sensitivity 60-100% in metastatic disease, 50% in early disease)
  • General circulating marker for neuroendocrine tumors (NETs)
  • False positives higher in reference ranges <20-fold

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 A, synaptophysin
  • May also stain for tumor-specific hormones – gastrin, glucagon, insulin, neuron-specific enolase (NSE), somatostatin
    • Positive staining not always associated with clinical syndrome
    • Consider staining for somatostatin receptors – SSTR2

Imaging Studies

• Multiphasic CT/MRI/ultrasound
  • Detects tumors >1.5 cm (many PNETs are small)
• Somatostatin-receptor scintigraphy (not useful in insulinomas)
• Bone scan if clinically indicated
• FDG-PET scan for poorly differentiated tumors

Prognosis

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

Differential Diagnosis

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

Screening

Monitoring

Clinical Background

Pancreatic neuroendocrine tumors (PNETs) are rare functional or nonfunctional tumors of pancreatic islet cells. PNETs account for <5% of all pancreatic tumors.

Epidemiology

• Incidence – 1.8-2.6/1,000,000
• Age – onset 40s-60s
  • Significant number of PNET patients are under the age of 35
• Sex – M>F
• Occurrence – usually sporadic (15% are associated with multiple endocrine neoplasia type 1 (MEN1)

Risk Factors

• Genetic – may be associated with MEN1, von Hippel-Lindau syndrome, or neurofibromatosis type 1 (NF1) peripheral

Pathophysiology

• Solid or cystic tumors located anywhere within the pancreas
• Tumors may be functional or nonfunctional
  • Functional tumors secrete hormones, producing classic clinical symptoms (eg, Verner-Morrison syndrome associated with vasoactive intestinal polypeptide [VIP] secretion)
  • Nonfunctional tumors may secrete hormones but do not cause symptoms
• Frequency of occurrence – nonfunctional > insulinoma > gastrinoma > glucagonoma > VIPoma > somatostatinoma
  • ~50% of PNETs are insulinomas, of which 90% are benign
  • 60-90% of gastrinomas are malignant
  • Molecular pathogenesis of pancreatic PNETs is incompletely understood
    • PNETs occur in 80-100% of patients with MEN1, 10-20% of patients with von-Hippel-Lindau syndrome, 10% of patients with NF1

Clinical Presentation

• Tumor increasingly identified incidentally by imaging
  • Nonfunctioning tumors tend to be large – 70% are >5 cm and of advanced stage at diagnosis; 60-80% have liver metastasis
• Patients may present with one of five common hormonal syndromes
  • Insulinoma
    • Most common secretory PNET to produce symptoms
  • Zollinger-Ellison syndrome – gastrinoma
    • Peptic ulcer disease
  • Glucagonoma
    • Mild diabetes mellitus (DM) with characteristic rash
  • Verner-Morrison syndrome – VIPoma
    • Watery diarrhea, hypokalemia, achlorhydria (WDHA syndrome)
  • Somatostatinoma syndrome
    • Diarrhea, cholelithiasis, DM

Treatment

• Control of symptoms – based on tumor type and hormone secreted
• Surgical resection
• Somatostatin analogues for glucagonomas and VIPomas
• Proton pump inhibitor (PPI) and H2-receptor drugs for gastrinoma
• Diazoxide for insulinoma
• Chemotherapy
  • Tyrosine kinase inhibitors
  • Interferon
  • Cytotoxics
  • mTOR inhibitors

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

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Pancreatic Polypeptide 0099436 Method: Quantitative Radioimmunoassay	Elevated in 50% of nonfunctional (ie, nonsyndromic) PNETs; 80% specificity
Glucagon by Immunohistochemistry 2003902 Method: Immunohistochemistry	IHC levels do not correlate with serum levels
Gastrin by Immunohistochemistry 2003896 Method: Immunohistochemistry	IHC levels do not correlate with serum levels
Insulin by Immunohistochemistry 2003972 Method: Immunohistochemistry	IHC levels do not correlate with serum levels
Neuron Specific Enolase, Polyclonal (NSE P) by Immunohistochemistry 2004052 Method: Immunohistochemistry	Identifies tissue of neuronal and neuroectodermal origin
Protein Gene Product (PGP) 9.5 by Immunohistochemistry 2004091 Method: Immunohistochemistry
Somatostatin by Immunohistochemistry 2004133 Method: Immunohistochemistry	IHC levels do not correlate with serum levels
Calcium, Ionized, Serum 0020135 Method: Ion-Selective Electrode/pH Electrode
Parathyroid Hormone, Intact with Calcium 0070172 Method: Quantitative Electrochemiluminescent Immunoassay
Prolactin 0070115 Method: Quantitative Chemiluminescent Immunoassay