Gastrinoma and Zollinger-Ellison Syndrome

Michael D. Smith, MD
The Operative Review of Surgery. 2023; 1:168-174.

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Table of Contents

Pathophysiology
Presentation
Diagnosis
Treatment

References

Pathophysiology

Definitions

  • Gastrinoma: Gastrin Secreting Neuroendocrine Tumor 1
  • Zollinger-Ellison Syndrome (ZES): Syndrome of Gastric Acid Hypersecretion Due to Gastrinoma 2

Distribution

  • Duodenum – Most Common Location 1,3
    • Sporadic Tumors: 50-88%
    • MEN-1-Associated Tumors: 70-100%
    • *Most Common in the First Portion
  • Pancreas: 20-25% 4
  • Other: 5-15% 1,5-7
    • Stomach
    • Jejunum
    • Liver
    • Biliary Tract
    • Peripancreatic Lymph Nodes
    • Ovary

Gastrinoma (Passaro) Triangle

  • Contain 60-90% of Tumors 9,10
  • Borders:
    • Junction of the Cystic & Common Bile Ducts
    • Junction of the Second & Third Portions of the Duodenum
    • Junction of the Neck & Body of the Pancreas

Size and Malignancy

  • Duodenal Tumors: 4,10
    • Usually Small in Size (< 1 cm) (60-90%)
    • Liver Metastases are Uncommon (5%)
  • Pancreatic Tumors: 4,10
    • Usually Large (≥ 3 cm) (70%)
    • Liver Metastases are Common (52%)
  • Over Half Are Malignant (60-90%) at the Time of Diagnosis 10-12
  • 20-30% are Associated with Multiple Endocrine Neoplasia Type 1 (MEN1) 3,13
    • Most Common PNET in MEN-1 Syndrome 14

Epidemiology

  • Average Age: 40 4
  • 55-56% are Male 4

Gastrinoma (Passaro) Triangle 8

Presentation

Peptic Ulcer Disease

  • Incidence: 73-98% 3,10
  • The Most Common Presenting Symptom
  • Due to Significantly Increased Basal Acid Output (BAO)
    • Typically 4-Fold Higher, Can Be Over 10-Fold Higher 10
  • Associated Symptoms:
    • Abdominal Pain
    • Bleeding
    • Stricture
    • Fistula
    • Perforation
  • Often Severe and Refractory to Initial Management with Proton Pump Inhibitors
  • Ulcer Location: 15
    • Proximal Duodenum: 75% – Most Common
    • Distal Duodenum: 14%
    • Jejunum: 11%
    • *Often Occur More Distal in the Duodenum/Jejunum than Sporadic Ulcers
  • Associated with Prominent Gastric Folds (94%) with Gastric Enterochromaffin-Like (ECL) Cell Hyperplasia 10

Additional Symptoms 3,10

  • Heart Burn (52-55%)
  • Diarrhea (60-75%)
  • Weight Loss (7-53%)
  • Nausea and Vomiting (20-30%)

Diagnosis

Diagnosis

  • Diagnosis is Frequently Delayed 4-7 Years Because ZES is Such an Uncommon Cause of PUD 16-18
  • Initial Screening: Elevated Fasting Serum Gastrin (FSG) and Measurement of Gastric pH 3,17,18
  • Additional Testing if Initial Findings are Not Diagnostic:
    • Secretin Stimulation Test
      • Secretin Normally Shows Minimal Change but Induces a Marked Gastrin Increase in ZES
    • Fasting Gastric Basal Acid Output (BAO) – Historical and Now Rarely Performed 3,19
  • Diagnostic Criteria: 10
    • FSG > 10x Upper Limit of Normal and Gastric pH ≤ 2
    • FSG < 10x Upper Limit of Normal and Secretin Stimulation Test Positive (≥ 120 pg/ml Increase)
    • FSG < 10x Upper Limit of Normal and Elevated BAO (> 15 mEq/hr)
  • Gastrin Measurement Requires Holding Any PPI for 3-7 Days Before Testing (PPIs Induce Hypergastrinemia) 20
  • If Unsafe to Hold PPI (Life-Threatening Bleeding, etc.): Consider Somatostatin Receptor Imaging for Diagnosis & Localization

TNM Staging

Localization

  • Initial Imaging: Noninvasive (CT or MRI)
  • Somatostatin Receptor Imaging 22,23
    • Consider if Initial Imaging Fails to Localize
    • Options:
      • Somatostatin (Octreotide) Receptor Scintigraphy (SRS) – Classic Test Used
      • Functional PET Scan (Ga-68 DOTATATE) – Becoming More Prevalent with Higher Sensitivity
  • If Noninvasive Imaging Fails: Invasive Imaging
    • Endoscopic Ultrasound (EUS) – Generally Preferred Next Step 24
    • Selective Arterial Secretin Stimulation with Hepatic Venous Sampling 25
    • Selective Visceral Angiography
  • Consider Surgical Exploration with Palpation or Intraoperative Ultrasound if High Suspicion but All Imaging Negative

PNET on Imaging: (A) CT, (B) EUS, (C) SRS, (D) Functional PET 26

Treatment

Surgical Resection (Treatment of Choice)

  • < 2-3 cm: Enucleation
    • Additional Requirements:
      • Single Lesion
      • ≥ 2-3 mm From the Main Pancreatic Duct (Reduce Leak Risk)
      • Well-Encapsulated
      • No Local Invasion
    • The Preferred Approach if Able
  • > 2-3 cm: Surgical Resection
    • Head/Neck: Pancreaticoduodenectomy
    • Body/Tail: Distal Pancreatectomy (Concurrent Splenectomy if Malignancy is Suspected)
    • Entire Pancreas: Total Pancreatectomy

Medical Management for Gastric Acid Hypersecretion

  • Measures:
    • High-Dose Proton Pump Inhibitor (PPI) – First Line 14,27,28
    • Somatostatin Analogs (SSAs) if PPIs Fail 29,30
      • Octreotide or Lanreotide
  • Used Preoperatively or for Patients that are Not Surgical Candidates or in Unresectable Metastatic Disease

Liver-Directed Therapy

  • Resection of Metastases if Able
  • Radiofrequency Ablation (RFA) or Cryoablation 31,32
  • Hepatic Artery Embolization 33

Additional Options in Surgically Unresectable Disease

  • Chemotherapy 34,35
  • Radiation Therapy 36,37
    • Pancreatic Neuroendocrine Carcinomas Were Previously Considered to be Resistant to Radiation

References

  1. National Cancer Institute. NIH.
  2. ZOLLINGER RM, ELLISON EH. Primary peptic ulcerations of the jejunum associated with islet cell tumors of the pancreas. Ann Surg. 1955 Oct;142(4):709-23; discussion, 724-8.
  3. Metz DC, Cadiot G, Poitras P, Ito T, Jensen RT. Diagnosis of Zollinger-Ellison syndrome in the era of PPIs, faulty gastrin assays, sensitive imaging and limited access to acid secretory testing. Int J Endocr Oncol. 2017;4(4):167-185.
  4. Berna MJ, Hoffmann KM, Serrano J, Gibril F, Jensen RT. Serum gastrin in Zollinger-Ellison syndrome: I. Prospective study of fasting serum gastrin in 309 patients from the National Institutes of Health and comparison with 2229 cases from the literature. Medicine (Baltimore). 2006 Nov;85(6):295-330.
  5. Norton JA, Alexander HR, Fraker DL, Venzon DJ, Gibril F, Jensen RT. Possible primary lymph node gastrinoma: occurrence, natural history, and predictive factors: a prospective study. Ann Surg. 2003 May;237(5):650-7; discussion 657-9.
  6. Jensen RT, Cadiot G, Brandi ML, de Herder WW, Kaltsas G, Komminoth P, Scoazec JY, Salazar R, Sauvanet A, Kianmanesh R; Barcelona Consensus Conference participants. ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms: functional pancreatic endocrine tumor syndromes. Neuroendocrinology. 2012;95(2):98-119.
  7. Norton JA, Foster DS, Blumgart LH, Poultsides GA, Visser BC, Fraker DL, Alexander HR, Jensen RT. Incidence and Prognosis of Primary Gastrinomas in the Hepatobiliary Tract. JAMA Surg. 2018 Mar 1;153(3):e175083.
  8. Blaus B. Wikimedia Commons (License: CC BY-SA 4.0) – Altered Image
  9. Stabile BE, Morrow DJ, Passaro E Jr. The gastrinoma triangle: operative implications. Am J Surg. 1984 Jan;147(1):25-31.
  10. Jensen RT, Ito T. Gastrinoma. 2020 Nov 21. In: Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, de Herder WW, Dhatariya K, Dungan K, Hofland J, Kalra S, Kaltsas G, Kapoor N, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, New M, Purnell J, Sahay R, Shah AS, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, editors. Endotext
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