Zollinger-Ellison Syndrome - Gastrinoma

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
  • Counseling and testing is recommended when multiple endocrine neoplasia type 1 (MEN1) is suspected or clinically diagnosed (NCCN, 2017)

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

• 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
• Renal failure
• Use of proton pump inhibitors or antacids

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