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, serum fasting (elevated in 99-100% of Zollinger-Ellison syndrome [ZES] patients)
  • Usually >200 pg/mL
  • >500-1,000 pg/mL virtually diagnostic
  • Elevated fasting serum gastrin in isolation is not diagnostic of ZES
• 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 not consistent with ZES diagnosis
• 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 on day of study
    • Acid suppressive medications discontinued at least 7-10 days prior to test
  • Baseline serum gastrin samples
    • Taken 15 minutes before and again 1 minute before secretin administration
  • Administration of pure porcine secretin (2 units/kg) intravenously over a 30-second time period
  • Serum gastrin samples
    • Initial samples at 2 and 5 minutes postinjection
    • Additional samples every 5 minutes for ≥20 minutes
  • Positive secretin stimulation test (increase in serum gastrin by >200 pg/mL) confirms the need to search for presence of gastrinoma
• Pancreatic polypeptide – increased in 35-40% of patients
• 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

• Gastroesophageal reflux disease
• MEN1 (Wermer syndrome)
• Peptic ulcer disease
• Helicobacter pylori infection
• Gastric outlet obstruction
• Pernicious anemia
• Short bowel syndrome
• Achlorhydria
• Pancreatic cancer
• Malabsorption syndromes
• Use of proton pump inhibitors

Monitoring

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 – 1/1,000,000
• Age – diagnosis in 30s-40s
• Sex – M:F, equal
• Occurrence – second most common pancreatic NET

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 – most often hepatic
• 25% of affected patients will present without peptic ulcer disease and have secretory diarrhea as the primary manifestation

Treatment

• Control gastric acid hypersecretion
  • Proton pump inhibitors and histamine H2-receptor antagonists are sufficient to control acid secretion and ulcerative disease in most patients
• Surgical resection
  • Generally for MEN1 tumors >2 cm (to reduce risk of metastasis)

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

Diagnostic Algorithm

  Zollinger-Ellison Syndrome Testing Algorithm