Zollinger-Ellison Syndrome - Gastrinoma

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.

Quick Answers for Clinicians

Which testing algorithms are related to this topic?

Diagnosis

Indications for Testing

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

Criteria for Diagnosis

  • National Comprehensive Cancer Network (NCCN), 2017
    • Elevated fasting serum gastrin (FSG) >10x upper limit of normal, and
    • Gastric pH <2

Laboratory Testing

  • Gastrin testing – patient should be off antacids and proton pump inhibitors 10 days to 2 weeks (may substitute H2 blockers until 48 hours before testing)
    • FSG
      • >10x upper limit of normal or >1000 pg/mL suggestive of gastrinoma
    • Stimulated gastrin testing (secretin, calcium) – value of provocative tests alone is limited (Oberg, 2017)
      • Secretin stimulation test – especially recommended for indeterminate FSG findings (200-1000 pg/mL)
        • Identify increase in serum gastrin after secretin administration
        • Positive secretin stimulation test (increase in serum gastrin by ≥120 pg/mL) confirms the need to search for presence of gastrinoma
        • ≥90% sensitive and specific
        • Normal cells are inhibited by secretin – gastrinoma cells secrete gastrin in response to secretin
        • Not recommended for patients with acute pancreatitis
        • Avoid external effects on gastrin release – must fast for 12 hours before beginning the study
        • Testing protocol
          • Collect serum gastrin samples – 15 minutes and 1 minute before secretin administration
          • Administer human secretin 0.4 mcg/kg of body weight intravenously over a 1 minute time period
          • Collect serum samples at 1, 2, 5, 10, and 30 minutes postinjection
          • Peak should occur at 10 minutes
      • Calcium stimulation testing – may be helpful for patients with a negative secretin test result
  • Gastric acid analysis (not available at ARUP Laboratories)
    • Evaluate stomach acid pH
    • Evaluate basal acid output (BAO)/secretion (National Cancer Institute [NCI], 2015; Oberg, 2017)
      • ≥10-15 mEq (mmol/L)/hr (or >5 mEq (mmol/L)/hr after acid-reducing surgery
      • Overnight acid output – ≥100 mmol
      • Ratio of BAO to maximum acid output (MAO) – ≥0.6
  • Human chorionic gonadotropin (HCG) levels – may be elevated in gastrinoma patients
  • General tumor markers – suggestive of pancreatic tumor (Oberg, 2017)
    • Chromogranin A – limited in diagnosis; typically indicated for follow-up (see Monitoring)
      • May be clinically informative but not recommended for diagnosis (Oberg, 2017; Strosberg, 2017)
      • Sensitivity – 60-90% in metastatic disease; 50% in early disease
  • Genetic testing

Histology

  • Definitive diagnosis requires biopsy and pathologist examination
    • Useful immunohistochemical stains may include chromogranin A, synaptophysin, and Ki-67 (Mib-1)
    • For detailed descriptions, including recommended tests, refer to ARUP’s Immunohistochemistry Stain Offerings

Imaging Studies

  • Computed tomography (CT) scan/endoscopic ultrasound/magnetic resonance imaging (MRI)
    • Identify tumor location and confirm diagnosis
    • Endoscopic ultrasound – 67% sensitivity
  • Somatostatin-receptor scintigraphy – ~85% sensitivity

Differential Diagnosis

Monitoring

  • Secretin test may be repeated for follow-up after surgery
  • General tumor markers – may be suggested for surveillance after resection (Oberg, 2017)
    • Chromogranin A – indicated for follow-up
    • Pancreatic polypeptide – serum test used in management of patients
    • Alpha (α) subunit pituitary glycoprotein hormones – serum test used in management of patients

Background

Epidemiology

  • Incidence – ~1/million; gastrinoma and somatostatinomas together account for ~10% of functional pancreatic neuroendocrine tumors (PNET) (National Comprehensive Cancer Network [NCCN], 2017)
  • Age – diagnosis in 30s-50s
  • Sex – M≥F (slight)
  • Occurrence – second most common PNET

Inheritance

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

Pathophysiology

  • NET 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
  • Large percent 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 present without peptic ulcer disease and have secretory diarrhea as the primary manifestation

ARUP Laboratory Tests

Aid in diagnosis of carcinoid and gastrinoma tumors

Patient should fast for 12 hours prior to collection and discontinue antacids and proton pump inhibitors for 10 days to 2 weeks

Aid in histologic diagnosis of gastrinoma

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

Aid in histologic diagnosis of gastrinoma

Determine mitotic rate of tissue

Stained and resulted by ARUP

Related Tests

Aid in monitoring but is not recommended for diagnosis of carcinoid tumors

May be useful in monitoring nonsecretory sympathetic and parasympathetic neuroendocrine tumors

Diagnostic testing for multiple endocrine neoplasia type 1 (MEN1)

Predictive testing for MEN1

Diagnostic testing for MEN1

Predictive testing for MEN1

Medical Experts

Contributor

Smy

 

Laura Smy, PhD, MLT (Canada)
Former Clinical Chemistry Fellow, University of Utah, Department of Pathology, School of Medicine
Contributor

References

Additional Resources