Zollinger-Ellison Syndrome - Gastrinoma

  • Diagnosis
  • Algorithms
  • Monitoring
  • Background
  • Lab Tests
  • References
  • Related Content

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

Zollinger-Ellison Syndrome Testing Algorithm

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

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

Gastrin 0070075
Method: Quantitative Chemiluminescent Immunoassay

Limitations

Proton pump inhibitor (PPI) treatment and atrophic gastritis may interfere with test 

Gastric Analysis 0020149
Method: Quantitative Titration

Limitations

If on PPI, must stop for 2 weeks  

Gastrin by Immunohistochemistry 2003896
Method: Immunohistochemistry

Chromogranin A by Immunohistochemistry 2003830
Method: Immunohistochemistry

Synaptophysin by Immunohistochemistry 2004139
Method: Immunohistochemistry

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

Ki-67 with Interpretation by Immunohistochemistry 2007182
Method: Immunohistochemistry

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

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

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

Guidelines

NCCN Clinical Practice Guidelines in Oncology, Neuroendocrine Tumors. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Sep 2015]

O'Toole D, Grossman A, Gross D, Fave G, Barkmanova J, O'Connor J, Pape U, Plöckinger U, Mallorca Consensus Conference participants, European Neuroendocrine Tumor Society. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: biochemical markers. Neuroendocrinology. 2009; 90(2): 194-202. PubMed

Protocol for the Examination of Specimens from Patients with Carcinoma of the Endocrine Pancreas. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: June 2012. College of American Pathologists (CAP). Northfield, IL [Accessed: Nov 2015]

Protocol for the Examination of Specimens from Patients with Neuroendocrine Tumors (Carcinoid Tumors) of the Small Intestine and Ampulla. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: June 2012. College of American Pathologists (CAP). Northfield, IL [Accessed: Sep 2015]

Protocol for the Examination of Specimens from Patients with Neuroendocrine Tumors (Carcinoid Tumors) of the Stomach. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: February 2010. College of American Pathologists (CAP). Northfield, IL [Accessed: Nov 2015]

Vinik A, Woltering E, Warner R, Caplin M, O'Dorisio T, Wiseman G, Coppola D, Go V, North American Neuroendocrine Tumor Society (NANETS). NANETS consensus guidelines for the diagnosis of neuroendocrine tumor. Pancreas. 2010; 39(6): 713-34. PubMed

Öberg K, Knigge U, Kwekkeboom D, Perren A, ESMO Guidelines Working Group. Neuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012; 23 Suppl 7: vii124-30. PubMed

General References

Arnold R. Diagnosis and differential diagnosis of hypergastrinemia. Wien Klin Wochenschr. 2007; 119(19-20): 564-9. PubMed

Batcher E, Madaj P, Gianoukakis A. Pancreatic neuroendocrine tumors. Endocr Res. 2011; 36(1): 35-43. PubMed

Epelboym I, Mazeh H. Zollinger-Ellison syndrome: classical considerations and current controversies. Oncologist. 2014; 19(1): 44-50. PubMed

Falchetti A, Marini F, Luzi E, Giusti F, Cavalli L, Cavalli T, Brandi M. Multiple endocrine neoplasia type 1 (MEN1): not only inherited endocrine tumors. Genet Med. 2009; 11(12): 825-35. PubMed

Oberg K. Pancreatic endocrine tumors. Semin Oncol. 2010; 37(6): 594-618. PubMed

Medical Reviewers

Last Update: December 2015