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
    • Gastrinoma (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
  • Molecular testing
    • MEN1 germline testing may be considered if family history of multiple tumors or clustering of PNET tumors in family

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

Screening

  • Once diagnosis has been established, screening for multiple endocrine neoplasia type 1 (MEN1) syndrome is necessary
    • Measure ionized Ca++, serum parathyroid hormone, and prolactin

Monitoring

  • Follow-up testing 3-12 months after resection and annually thereafter
    • History and physical exam
    • Tumor markers – based on syndrome
    • Multiphasic CT/MRI
    • Chromogranin A – may be useful in monitoring response to therapy

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
    • Gastrinoma (Zollinger-Ellison syndrome)
      • Peptic ulcer disease
    • Glucagonoma
    • Verner-Morrison syndrome – VIPoma
      • Watery diarrhea, hypokalemia, achlorhydria (WDHA syndrome)
    • Somatostatinoma syndrome
      • Diarrhea, cholelithiasis, DM
  • Patients may have heritable disorders as etiology (eg, MEN1) for these tumors

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
Test Name and Number Recommended Use Limitations Follow Up
Electrolyte Panel 0020410
Method: Quantitative Ion-Selective Electrode/Enzymatic

General test for PNET; nonspecific test for VIPoma and Zollinger-Ellison syndrome (ZES)

   
Glucose, Plasma or Serum 0020024
Method: Quantitative Enzymatic

Use to diagnose hypoglycemia that is associated with insulinoma

   
Insulin, Fasting 0070063
Method: Quantitative Chemiluminescent Immunoassay

Aids in the diagnosis of insulinoma

   
Proinsulin, Intact 0070112
Method: Quantitative Chemiluminescent Immunoassay

Aids in the diagnosis of insulinoma

Helps rule out insulin abuse

   
C-Peptide, Serum or Plasma 0070103
Method: Quantitative Chemiluminescent Immunoassay

Aids in the diagnosis of insulinoma

Helps rule out insulin abuse

   
Gastrin 0070075
Method: Quantitative Chemiluminescent Immunoassay

Aids in the diagnosis of gastrinoma

Poor diagnostic tool, but pretreatment values useful in assessing treatment and detecting recurrence

In 20% of cases gastrin may only be 5-20% above reference range

Patient should be fasting

Patients should be off protein pump inhibitor (PPI) and H2-receptor blockers for 5-7 days

 
Glucagon 0099165
Method: Quantitative Radioimmunoassay
Aids in the diagnosis of glucagonoma    
Vasoactive Intestinal Peptide 0099435
Method: Quantitative Radioimmunoassay

Aids in the diagnosis of VIPoma

Patients frequently present with VIP ≤20-50% over reference range

 
Somatostatin Quantitative, Plasma 2010001
Method: Quantitative Extraction/Immunoassay
Aids in the diagnosis of somatostatinoma

May be elevated in atrophic gastritis

 
Multiple Endocrine Neoplasia Type 1 (MEN1) Sequencing and Deletion/Duplication 2005360
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Diagnosis and presymptomatic identification of multiple endocrine neoplasia type 1 (MEN1)

Clinical sensitivity – combined testing ~94% (90% sequencing, 4% deletion/duplication)

Diagnostic errors can occur due to rare sequence variations

Regulatory region mutations, deep intronic mutations, breakpoints of large deletions/duplications, and mutations in genes other than MEN1 are not evaluated

 
Chromogranin A 0080469
Method: Quantitative Enzyme Immunoassay

May be helpful in determining metastatic disease

Monitor PNET

May be elevated due to PPI therapy or impaired renal function

Results obtained with different assay methods or kits cannot be used interchangeably

 
Chromogranin A by Immunohistochemistry 2003830
Method: Immunohistochemistry

Aid histologic diagnosis of PNETS

Stained and returned to client pathologist; consultation available if needed

   
Synaptophysin by Immunohistochemistry 2004139
Method: Immunohistochemistry

Aid histologic diagnosis of PNETS

Stained and returned to client pathologist; consultation available if needed

   
Ki-67 with Interpretation by Immunohistochemistry 2007182
Method: Immunohistochemistry

Aid in determining tumor grade

High mitotic index indicates poor prognosis

Stained and resulted by ARUP

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Pancreatic Polypeptide 0099436
Method: Quantitative Radioimmunoassay

Elevated in 50% of nonfunctional (ie, nonsyndromic) PNETs; 80% specificity

Gastrin by Immunohistochemistry 2003896
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
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
Multiple Endocrine Neoplasia Type 1 (MEN1) Sequencing 2005359
Method: Polymerase Chain Reaction/Sequencing

Acceptable initial test, but does not detect deletions/duplications

Clinical sensitivity – 90%

Multiple Endocrine Neoplasia Type 1 (MEN1) Deletion/Duplication 2005346
Method: Polymerase Chain Reaction/Multiplex Ligation-dependent Probe Amplification

Use if no mutations detected by sequencing

Clinical sensitivity – 4%