Zollinger-Ellison Syndrome and MEN Syndromes — Gastrinoma, MEN1, MEN2A and MEN2B

Gastrinomas are functional neuroendocrine neoplasms that secrete gastrin autonomously. The resulting hypergastrinaemia drives gastric acid hypersecretion, severe peptic ulcer disease and secretory diarrhoea; this combination is Zollinger-Ellison syndrome (ZES). It was described in 1955 by Robert Zollinger and Edwin Ellison in patients with refractory proximal jejunal ulcers and marked acid hypersecretion.

Gastrinomas arise from enteroendocrine G cells, most often within the gastrinoma triangle: bounded superiorly by the confluence of the cystic and common bile ducts, inferiorly by the second and third parts of the duodenum, and medially by the neck of the pancreas. About 70 to 90 percent arise in the duodenum and 10 to 30 percent in the pancreas. Duodenal tumours are usually smaller and more likely to spread to regional lymph nodes than pancreatic ones. Gastrinoma is the most common functional neuroendocrine tumour of the duodenum and the second most common pancreatic neuroendocrine tumour.

• Sporadic (about 80 percent): typically diagnosed around age 50, slight male predominance.
• MEN1-associated (20 to 30 percent): present earlier, often at 20 to 30 years; tumours are usually multiple, small (under 1 cm) duodenal lesions.
• Incidence: rare, about 0.5 to 2 per million per year.
• Behaviour: indolent growth but most are malignant, and about 60 percent have metastasized at diagnosis.

Gastrin stimulates parietal cells through cholecystokinin B (CCK-B) receptors to increase HCl production. Normal gastrin secretion is switched off by intragastric acid, but a gastrinoma secretes independently of luminal pH, so acid output stays high. Chronic stimulation also causes hyperplasia of fundic parietal cells. The excess acid overwhelms mucosal defences and causes refractory ulcers, perforation, bleeding and reflux.

Diarrhoea and steatorrhoea occur because the acid inactivates pancreatic enzymes and bile salts, impairing lipid digestion and absorption. A key trap: PPIs relieve symptoms and can mask the diagnosis, so patients are often diagnosed late.

Diagnosis combines biochemistry (gastrin and gastric pH) with imaging for localisation. Stop PPIs for at least 1 week and H2-receptor antagonists for 48 hours before testing, because they interfere with gastrin levels.

• Acid control: high-dose PPIs, 2 to 3 times standard GERD doses (for example omeprazole 60 mg/day or equivalent), to cut acid output by more than 90 percent; prevents perforation and bleeding.
• Localised sporadic tumour: surgical resection is the cornerstone; cure rates can exceed 70 to 80 percent, and 5-year survival can approach 90 percent after curative resection without metastases. Small lesions may be enucleated; larger ones may need pancreaticoduodenectomy.
• MEN1-associated: tumours are multifocal and often extrapancreatic, so surgery is usually reserved for tumours over 2 cm (metastasis risk 60 to 80 percent versus under 20 percent for smaller tumours). Parathyroidectomy is recommended when ZES coexists with primary hyperparathyroidism, because hypercalcaemia worsens acid secretion.
• Metastatic disease: somatostatin analogues (octreotide, lanreotide), everolimus or sunitinib, PRRT with 177Lu-dotatate, and chemotherapy (streptozocin, 5-FU or temozolomide-based) with modest response rates.

MEN1 is an autosomal dominant, highly penetrant syndrome caused by germline inactivating mutations of the MEN1 (menin) gene on chromosome 11. It affects the parathyroid glands, anterior pituitary and gastro-entero-pancreatic neuroendocrine tissue. About 90 percent of cases are inherited and 10 percent are de novo, and roughly 20 percent of MEN1 families have no detectable MEN1 mutation.

• Primary hyperparathyroidism (about 90 percent) is the most common and usually the first manifestation, often in the second decade, with multigland nodular hyperplasia and more severe bone disease than sporadic disease despite milder biochemistry.
• Pancreatic neuroendocrine tumours (about 60 percent): non-functioning tumours are most common and are the most frequent cause of death; gastrinoma is the most frequent functioning tumour; insulinoma is second (10 to 30 percent of pancreatic NETs) and presents with hypoglycaemia.
• Pituitary adenomas (about 40 percent): most commonly prolactin-secreting, then growth hormone (see acromegaly and pituitary tumours).
• Other tumours: thymic and bronchial carcinoids and other endocrine or non-endocrine tumours.

Diagnosis needs two of the three primary tumour types, or one MEN1 tumour plus an affected first-degree relative, or a pathogenic MEN1 mutation. Parathyroid surgery is debated: total parathyroidectomy with forearm autograft lowers persistent disease but carries a higher risk of hypoparathyroidism (22 to 36 percent versus about 10 percent after subtotal parathyroidectomy). Imaging screening for pancreatic NET is recommended from age 10.

MEN2 is caused by gain-of-function germline mutations of the RET proto-oncogene (chromosome 10q11.21), inherited as autosomal dominant. RET encodes a receptor tyrosine kinase important in neural-crest-derived tissues. MEN2A (Sipple syndrome) accounts for about 95 percent of cases; MEN2B (mucosal neuroma syndrome) is extremely rare. In both, nearly 100 percent develop medullary thyroid cancer (MTC) and up to 50 percent develop phaeochromocytoma.

• RET testing is indicated in every patient with MTC (even if apparently sporadic), first-degree relatives, patients with cutaneous lichen amyloidosis, and all pheochromocytoma or paraganglioma cases. Hotspot testing starts with exons 10 and 11, then 8, 13, 14, 15 and 16.
• Surgery: total thyroidectomy with bilateral central neck dissection for MTC without nodal disease; prophylactic thyroidectomy is timed by the RET mutation risk category, to act before the tumour spreads.
• Phaeochromocytoma screening: plasma free or 24-hour urinary metanephrines and normetanephrines, then CT or MRI. Test before any procedure, including thyroidectomy, or pregnancy, to avoid a hypertensive crisis. See adrenal disorders.
• Hyperparathyroidism: check albumin-corrected or ionised calcium at diagnosis in RET carriers; disease in MEN2A is often mild and asymptomatic.
• Follow-up: calcitonin and CEA 3 months after surgery; calcitonin above 150 pg/mL after thyroidectomy should prompt imaging for distant disease.

• Fasting gastrin above 1,000 pg/mL is diagnostic; 100 to 1,000 pg/mL is non-specific and common with PPIs. Stop PPIs first.
• High gastrin plus high acid (pH 2 or below) = gastrinoma; high gastrin plus high pH = atrophic gastritis or PPI effect.
• Most gastrinomas are duodenal (70 to 90 percent), and duodenal tumours are smaller and more likely to spread to regional nodes than pancreatic ones.
• MEN1 gene is a tumour suppressor (loss of function); RET is an oncogene (gain of function).
• MEN2B has no hyperparathyroidism; MEN2A has it in about 25 percent.
• Most common manifestation of MEN1 is hyperparathyroidism; most common functioning pancreatic tumour is gastrinoma; most common pituitary tumour is prolactinoma.
• Screen for phaeochromocytoma before thyroid or any surgery in MEN2.