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

  • Testing for nonfunctional tumors
    • 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
    • Neuron specific enolase (NSE)
    • Pancreatic polypeptid
  • For specific functioning syndrome use clinical presentation to order laboratory testing 
    • Insulinoma – glucose, insulin, c-peptide
    • Gastrinoma (Zollinger-Ellison syndrome) – gastrin, gastrin pH, stimulation testing
      • Patient should be off acid-suppressive medication for at least 7-10 days prior to testing
    • Glucagonoma – glucose, glucagon
    • VIPoma – vasoactive intestinal polypeptide (VIP), electrolytes
    • Somatostatinoma – somatostatin

Genetic testing

  • MEN1 germline testing – consider if at least two MEN1-associated tumors, family history of multiple tumors or clustering of PNET tumors in family
  • Other testing based on family history and presentation (eg, von Hippel-Lindau syndrome, neurofibromatosis type 1)

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, NSE, somatostatin
      • Positive staining not always associated with clinical syndrome (so-called nonfunctioning tumors)
      • 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)
  • Endoscopic ultrasound (EUS)
  • 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

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 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

Risk Factors

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

Pathophysiology

  • Solid or cystic tumors located anywhere within the pancreas
  • Tumors may be nonfunctional (most PNETs) or functional
    • Functional tumors secrete hormones, producing classic clinical syndromes (eg, Verner-Morrison syndrome associated with vasoactive intestinal polypeptide [VIP] secretion)
    • Nonfunctional tumors may secrete hormones but do not cause symptoms
      • Includes pancreatic polypeptidoma (PPoma)
  • Frequency of occurrence – nonfunctional > insulinoma > glucagonoma > gastrinoma or somatostatinoma > VIPoma > cholecystokininoma (CCKoma)
    • Up to 70% of PNETs are insulinomas, of which 90% are benign (NCCN, 2014)

Clinical Presentation

  • Tumor increasingly identified incidentally from findings on imaging or imaging performed as a result of obstructive symptoms
    • Most tumors are indolent with few symptoms
    • Nonfunctioning tumors tend to be large – 70% are >5 cm and of advanced stage at diagnosis; 60-80% have liver metastasis
      • Pancreatic polypeptidoma – nonfunctioning
  • Patients may present with symptoms of a hormonal syndrome
    • Insulinoma
      • Hypoglycemia, weakness
    • Gastrinoma (Zollinger-Ellison syndrome)
      • Peptic ulcer disease – recurrent, severe
    • Glucagonoma
      • Mild glucose intolerance, necrolytic migratory erythema, hypoaminoacidemia
    • VIPoma  (Verner-Morrison syndrome)
      • Watery diarrhea, hypokalemia, achlorhydria (WDHA syndrome)
    • Somatostatinoma
      • Steatorrhea, cholelithiasis, hyperglycemia, achlorhydria
  • Patients may have heritable disorders as etiology (eg, MEN1) for these tumors

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
Glucose, Plasma or Serum 0020024
Method: Quantitative Enzymatic

Diagnose hypoglycemia that is associated with insulinoma or hypoglycemia associated with glucagonoma

   
Insulin, Fasting 0070063
Method: Quantitative Chemiluminescent Immunoassay

Aids in the diagnosis of insulinoma

   
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
Electrolyte Panel 0020410
Method: Quantitative Ion-Selective Electrode/Enzymatic

General test for PNET

Nonspecific test for VIPoma and Zollinger-Ellison syndrome (ZES)

Proinsulin, Intact 0070112
Method: Quantitative Chemiluminescent Immunoassay

Aids in the diagnosis of insulinoma

Helps rule out insulin abuse

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%