Zollinger-Ellison Syndrome - Gastrinoma

Diagnosis

Indications for Testing

  • Refractory peptic ulcer disease
  • Multiple peptic ulcers
  • Familial peptic ulcer disease
  • Peptic ulcer disease with diarrhea

Laboratory Testing

  • Gastrin testing – patient must be off proton pump inhibitors ≥1 week
    • Basal gastrin fasting
      • Usually >10x normal
      • Elevated fasting serum gastrin in isolation is not diagnostic of Zollinger-Ellison syndrome (ZES)
    • Stimulated gastrin
      • Secretin stimulation test (90% sensitive and specific) – best test to diagnose gastrinoma
        • Identify increase in serum gastrin after secretin administration
        • Not recommended for patients with acute pancreatitis
        • Avoid external effects on gastrin release – must fast 12 hours on day of study
      • Baseline serum gastrin samples
        • Taken 15 minutes before and again 1 minute before secretin administration
      • Administration of human secretin (ChiRhoStim) – 0.4 mcg/kg of body weight intravenously over a 1 minute time period
      • Serum gastrin samples
        • Samples at 1, 2, 5, 10, and 30 minutes postinjection
        • Additional samples every 5 minutes for ≥20 minutes
      • Positive secretin stimulation test (increase in serum gastrin by ≥100 pg/mL) confirms the need to search for presence of gastrinoma
  • Gastric acid analysis – increased basal acid output/secretion (BAO) ≥15 mEq (mmol/L)/hr or >5 mEq (mmol/L)/hr after acid-reducing surgery
    • If BAO measurement unavailable, measure pH of gastric fluid
      • pH ≥2 inconsistent with ZES diagnosis
  • Chromogranin A – may be helpful
  • Genetic – counseling and testing if MEN1 suspected

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, Ki-67 (Mib-1)
    • Tumor-specific confirmation – gastrin
    • Other available stains include neuron specific enolase, polyclonal (NSE P), and protein gene product (PGP) 9.5

Imaging Studies

  • CT scan/endoscopic ultrasound/MRI
    • Identify tumor location and confirm diagnosis
    • Endoscopic ultrasound – 67% sensitivity
  • Somatostatin-receptor scintigraphy – ~85% sensitivity

Differential Diagnosis

Monitoring

  • Secretin test may be repeated during follow-up of curative surgery
  • Consider chromogranin A

Clinical Background

Zollinger-Ellison syndrome (ZES) is characterized by refractory peptic ulcer disease, diarrhea, and gastric acid hypersecretion as a result of a functional pancreatic or duodenal neuroendocrine tumor (NET). ZES is also referred to as gastrinoma.

Epidemiology

  • Incidence – ~1/million (~10% of functioning pancreatic NETs [PNET] [NCCN, 2015])
  • Age – diagnosis in 30s-50s
  • Sex – M≤F (slight)
  • Occurrence – second most common PNET

Inheritance

  • Most tumors are sporadic, although 20-30% are genetic
  • Multiple endocrine neoplasia type 1 (MEN1, Wermer syndrome) – heritable disorder with increased risk for NETs
    • Parathyroid gland hyperplasia or tumor, endocrine tumors of the pancreas or duodenum, and endocrine tumors of the pituitary gland
    • Autosomal dominant

Pathophysiology

  • Neuroendocrine tumor that secretes gastrin
  • Gastrin stimulates parietal gastric cells to increase in number
  • Increased number of parietal cells increases basal and maximal acid secretion
  • Increased acid secretion leads to ulcers and diarrhea
  • Most tumors (≥80%) occur in the duodenum and in the head of the pancreas
  • Multiple tumors are frequently present
  • Approximately 50-60% are malignant and metastasize

Clinical Presentation

  • Diagnosis is delayed an average of 4-6 years after symptom onset
  • Abdominal pain with recurrent peptic ulcer disease
    • Multiple ulcers common
    • Ulcers are refractory to therapy
  • Gastroesophageal reflux disease, possibly esophageal stenosis or Barrett mucosa
  • Diarrhea/steatorrhea – caused by acid secretion that inactivates pancreatic lipase and bile salts
  • Hypercalcemia – if associated with MEN1
  • Metastatic disease – often hepatic; most common presentation
  • 25% of affected patients will present without peptic ulcer disease and have secretory diarrhea as the primary manifestation

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
Gastrin 0070075
Method: Quantitative Chemiluminescent Immunoassay

Aids in diagnosis of carcinoid and gastrinoma tumors

Patient should be fasting

Proton pump inhibitor (PPI) treatment and atrophic gastritis may interfere with test  
Gastric Analysis 0020149
Method: Quantitative Titration

Use in diagnosis of ZES

If on PPI, must stop for 2 weeks   
Gastrin by Immunohistochemistry 2003896
Method: Immunohistochemistry

Aid in histologic diagnosis of gastrinoma

Stained and returned to client pathologist for interpretation; consultation available if needed

   
Chromogranin A by Immunohistochemistry 2003830
Method: Immunohistochemistry

Aid in histologic identification of neuroendocrine tissue

Stained and returned to client pathologist; consultation available if needed

   
Synaptophysin by Immunohistochemistry 2004139
Method: Immunohistochemistry

Aid in histologic diagnosis of gastrinoma

Stained and returned to client pathologist; consultation available if needed

   
Cytokeratin 7 (CK 7) by Immunohistochemistry 2003854
Method: Immunohistochemistry

Aid in histologic diagnosis of gastrinoma

Stained and returned to client pathologist; consultation available if needed

   
Ki-67 with Interpretation by Immunohistochemistry 2007182
Method: Immunohistochemistry

Aid in grading of NET

Determines mitotic rate of tissue

Stained and resulted by ARUP

   
Neuron Specific Enolase, Polyclonal (NSE P) by Immunohistochemistry 2004052
Method: Immunohistochemistry

Aid in histologic identification of neural and neuroendocrine tissue

Stained and returned to client pathologist; consultation available if needed

   
Pan Cytokeratin (AE1,3) by Immunohistochemistry 2003433
Method: Immunohistochemistry

Aid in histologic identification of epithelial tissue

Stained and returned to client pathologist; consultation available if needed

   
Protein Gene Product (PGP) 9.5 by Immunohistochemistry 2004091
Method: Immunohistochemistry

Aid in histologic diagnosis of gastrinoma

Stained and returned to client pathologist; consultation available if needed