Zollinger-Ellison syndrome

Clinical triad consisting of

• Gastric acid hypersecretion
• Severe PUD
• Gastrin-producing neuroendocrine tumours ('gastrinomas')

Epidemiology

• Mean age at diagnosis 50yo

Pathophysiology

• The clinical syndrome caused by pancreatic/duodenal gastrinoma-secreting neuroendocrine tumours
• Most (80%) of gastrinomas are within the 'gastrinoma triangle', which is between the cystic duct-CBD junction, the pancreas body-neck junction, and the junction between D2 and D3
• Can metastasise to lymph nodes or liver, but slow-growing
• 20-30% of patients with ZES have MEN 1, and 50% of patients with MEN 1 have ZES

Presentation

• Symptoms are produced by hypergastrinaemia
  • Abdominal pain/PUD (>80%)
    • ZES is associated with multiple ulcers, ulcers distal to D2, and PPI resistance
  • Diarrhoea
  • Weight loss
  • Steatorrhoea
  • Oesophagitis
• Responsible for somewhere less than 1% of PUD
• Gastroscopy:
  • D2 ulcers
  • Thickened gastric folds, erosions (often duodenal), oesophagitis, hypervascular mucosa
  • Nodular lesions can be carcinoid tumours

Investigation for suspected ZES

• Indications:
  • Intractable peptic ulcers (D2, and especially jejunal)
  • Severe oesophagitis
  • Persistent secretory diarrhoea
• Fasting serum gastrin >10x ULN (>1000pg/mL) and gastric pH <2 is diagnostic
  • Note that serum gastrin is falsely elevated with H2 blockers/PPIs on board, and in H. pylori infection and renal failure. Generally try to stop PPI for 2/52 prior.
  • Achlorhydria can also impact results - that's why you need to check stomach pH
    • pH >3 excludes ZES, while pH<2 is consistent
  • Provocative tests (before and after IV secretin) are generally not required, but can be done with equivocal results. An increase >200pg/mL above basal levels is suggestive of gastrinoma.
• Endoscopy
  • Prominent gastric rugal folds (due to trophic effect of hypergastrinaemia on fundus)

Investigation of diagnosed ZES

• Workup for MEN 1 - pituitary and hyperparaythyroidism
  • Serum parathyroid
  • Calcium
  • Prolactin
• CT triple-phase
  • Low sensitivity with tumours <1cm
• DOTATATE PET
• EUS sometimes helpful
• If still unable to localise, can do surgical exploration

Management

• Medical
  • High-dose PPI
  • Good for unresectable or metastatic disease
• Surgical
  • All patients with sporadic gastrinoma but no unresectable mets should have an exploratory curative laparotomy
    • If not localised pre-operatively, explore the entire abdomen, from underside of diaphragm to the pelvic floor, with particular attention to the liver, right subhepatic and paraduodenal area, and pelvic cul-de-sac and ovaries, and small bowel and colon. Perform intra-operative USS and check duodenum.
    • Excise regional nodes too - aim for >10
  • In more advanced disease, cytoreductive surgery is worth considering. Can do stuff like ablation of mets
• Radiotherapy
  • Possibly useful in palliative patients
• Chemotherapy
  • Indications
    • Unresectable or recurrent disease
  • Somatostatin analogues and/or a streptozocin/doxorubicin-based CTX regime
• Treatment of mets
  • Consider liver-directed therapies - RFA, cryoablation, embolisation, resection, or transplantation
• Patients with MEN 1
  • Parathyroidectomy should be done prior to gastrinomaectomy
  • In patients with MEN1 - only resect if identifiable gastrinoma >2cm

Prognosis

• If bilobar liver mets, 15% ten year survival (better predictor of survival than lymph node metastases)
• Long-term cure rates after curative resection of non-metastatic tumours are ~50%
• However patients have been known to live >20 years with residual disease