Gastrinoma

Overview

Definition

A gastrinoma is a neuroendocrine tumor associated with Zollinger-Ellison syndrome (ZES), which secretes large amounts of gastrin and overstimulates gastric acid production causing severe peptic ulcers.

Epidemiology

• Annual incidence 0.5–2 per million
• More common in men
• Seen in patients 30–50-years-old
• Duodenum most common location (70%)
• Pancreatic gastrinomas are usually located at the head of the pancreas.

Etiology

• Up to 80% arise sporadically
• Genetics:
  • 20%–30% associated with MEN 1 (multiple endocrine neoplasia 1); commonly multifocal
  • 1%–10% have another hormone-secreting tumor.
• ZES: caused by excessive gastrin production

Pathophysiology

Gastrinoma

Gastrinomas are neuroendocrine tumors arising in the digestive tract.

• Location:
  • 70%–90% found in Passaro’s triangle:
    • Junction of cystic and common bile ducts
    • 2nd and 3rd portions of duodenum
    • Neck and body of pancreas
  • Arise from: 
    • Duodenum (most common)
    • Jejunum 
    • Stomach
    • Pancreas
    • Lymph nodes
• Histology:
  • Well-differentiated 
  • Degree of malignancy not determined by morphologic/histologic appearance alone
  • Tumoral cells: 
    • Arranged in solid, trabecular, gyriform, or glandular pattern
    • Neurosecretory granules may contain other hormones besides gastrin (vasoactive intestinal peptide, glucagon).
    • Express synaptophysin and chromogranin
  • Tumors may produce ectopic hormone, but it is not processed to a biologically active form.
  • Only considered gastrinoma if clinically associated with ZES

Zollinger-Ellison syndrome (ZES)

Gastrinomas secrete excessive gastrin:

• Stimulates parietal and histamine-secreting enterochromaffin-like (ECL) cells
• Results in high (4-fold to 10-fold) levels of gastric acid

Excessive gastric acid results in:

• Peptic ulcer disease (PUD):
  • Present in > 90% of patients with ZES
  • 75% in 1st portion of duodenum
  • Often multiple, recurrent, and refractory to proton pump inhibitors (PPIs)
  • Sometimes in unusual locations (beyond 1st or 2nd folds of duodenum)
• Chronic diarrhea:
  • Low pH of intestinal contents inactivates pancreatic digestive enzymes → malabsorption and steatorrhea
  • Gastrin inhibits absorption of sodium and water by intestines → secretory diarrhea

Diagnosis

History

• PUD:
  • Abdominal pain
  • Dyspepsia
  • Nausea/vomiting
• Gastrointestinal complications of PUD:
  • Bleeding
  • Strictures
  • Perforations
• Gastroesophageal reflux/heartburn
• Diarrhea/steatorrhea
• Weight loss (due to malabsorption)
• Past medical history:
  • Multiple, refractory, recurrent, or unusual peptic ulcers
  • Diarrhea responsive to PPIs
  • Personal or family history of MEN 1

Laboratory studies

• Fasting gastrin level:
  • ≥ 10x normal with stomach pH < 2 is diagnostic of ZES.
  • < 10x normal is non-specific; may be associated with other causes of hypergastrinemia.
• Secretin stimulation test:
  • Used if gastrin levels < 10-fold elevated
  • Perform off of PPI
  • Should not be performed in patients with severe, active ZES (may cause life-threatening complications)
  • Serum gastrin peaks 10 minutes after secretin administration
  • Criteria for positive test:
    • Gastrin increase > 120 pg/mL over baseline fasting level
    • 50% increase in gastrin level

Tumor localization

If ZES is medically diagnosed, a gastrinoma must be identified.

• Imaging:
  • Abdominal computed tomography (CT) scan
  • Magnetic resonance imaging (MRI)
  • Somatostatin receptor scintigraphy (SRS): using radioactively labeled octreotide
  • Angiography or selective arterial stimulation: if cannot be localized with CT, MRI, or SRS
• Endoscopy:
  • Shows peptic ulcers 
  • Thickened gastric folds
  • May show duodenal tumor
• Surgical exploration: sometimes only way to localize tumor

Management

Medical management

• PPIs: Start at high dose and taper as needed.
• Somatostatin analogs (octreotide, lanreotide):
  • If PPIs are ineffective
  • Response is poorly predictable.

Surgery

•  Definitive cure for resectable tumors:
  • Sporadic gastrinomas without metastatic spread
  • Not for gastrinomas that are part of MEN 1 as they are often multifocal
• Enucleation is the preferred modality.
• Sometimes distal pancreatectomy or partial pancreatic head resection are required.

Metastatic disease

• 60%–90% of gastrinomas are malignant.
• Metastases are major sources of morbidity and mortality.
• Most common site of metastasis is liver, followed by bone.
• Therapies:
  • Somatostatin analogs
  • Chemotherapy (streptozocin, doxorubicin)
  • Liver-directed therapies:
    • Resection
    • Hepatic artery embolization
    • Ablation therapies

Prognosis

• Liver metastasis: 10-year survival is 30%.
• Patients with MEN 1 have significantly lower rate of metastatic disease and higher overall survival (100% at 20 years).
• Lower baseline serum gastrin correlates with better prognosis.

Differential Diagnosis

• PUD: ulceration of the mucosal lining of the stomach or duodenum; typically due to Helicobacter pylori infection or use of nonsteroidal antiinflammatory drugs (NSAIDs). The most common symptom of both duodenal and gastric ulcers is epigastric pain. Diagnosis is confirmed by endoscopy. Sporadic peptic ulcers usually respond well to treatment regimens with antibiotics and PPIs.
• Malabsorption: malfunction of the intestinal wall resulting in insufficient absorption of breakdown products. Malabsorption may present as diarrhea, steatorrhea, abdominal distention, flatulence, weight loss, anemia, vitamin deficiencies, and/or failure to thrive. Diagnosis is established by a combination of stool studies, blood work, and sometimes endoscopy and imaging. Treatment is typically supportive.
• VIPoma: a neuroendocrine tumor, associated with MEN 1 that secretes vasoactive intestinal polypeptide (VIP). Presentation includes chronic diarrhea, flushing, and wheezing. Diagnosis is established by measuring blood and urine levels of VIP. Treatment consists of surgical tumor removal and symptom management.
• Carcinoid syndrome: a constellation of symptoms associated with carcinoid tumor production of serotonin and other substances. Presentation includes diarrhea, flushing, and wheezing. Diagnosis is established by serotonin metabolite measurement and imaging to confirm tumor presence. Treatment includes surgical resection and symptomatic management.