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 ≥110 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 [NCCN, 2014])
  • Age – diagnosis in 30s-40s
  • Sex – M:F, equal
  • 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

Use in diagnosis of ZES

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