MEN Screening & Neuroendocrine Tumors (Clinical)

When to suspect an inherited syndrome

Clues. Endocrine tumors that arise at a young age, are bilateral or multifocal, involve two or more glands, or cluster in a family point to a germline syndrome. The major syndromes are autosomal dominant, so a confirmed mutation triggers cascade testing of first-degree relatives and lifelong, gene-directed surveillance. MEN1 results from loss of the tumor suppressor menin; MEN2 from activating mutations of the RET proto-oncogene, a receptor tyrosine kinase.

MEN1

Hyperparathyroidism. Primary hyperparathyroidism is the most common and usually the earliest manifestation, present in more than 90% of carriers by age 50. It is asymmetric hyperplasia of all glands rather than a single adenoma, so the operation is subtotal (3½-gland) parathyroidectomy or total parathyroidectomy with autotransplantation, plus transcervical thymectomy for supernumerary glands. Recurrence is common.

Duodenopancreatic NETs. Most are nonfunctioning; gastrinoma, often multiple small duodenal tumors, is the leading functional tumor, followed by insulinoma. Malignant NETs are the leading cause of MEN1-related death. Because calcium stimulates gastrin release, correcting hypercalcemia first eases acid control in MEN1-associated Zollinger–Ellison syndrome.

Pituitary and testing. Pituitary adenomas occur in about a third of patients, most often prolactinomas. Offer MEN1 testing for two or more MEN1 tumors, a relative who carries the mutation, hyperparathyroidism before about age 30 or with multigland disease, gastrinoma, or multiple pancreatic NETs.

MEN2 and medullary thyroid carcinoma

MEN2A. Medullary thyroid carcinoma (MTC) develops in nearly all carriers, pheochromocytoma in up to half (often bilateral and epinephrine-secreting), and primary hyperparathyroidism in about 20–30%.

MEN2B. MTC appears in infancy and is the most aggressive form; pheochromocytoma occurs in about half. The phenotype is recognizable: neuromas of the lips, tongue, and eyelids giving "bumpy" lips, a marfanoid build without lens or aortic disease, intestinal ganglioneuromatosis with constipation or megacolon, and medullated corneal nerves. Hyperparathyroidism is not part of MEN2B.

Medullary thyroid carcinoma. MTC arises from parafollicular C cells, secretes calcitonin and CEA (tumor markers), and has calcitonin-derived amyloid stroma. About 25% of cases are hereditary, and a few percent of patients with no known family history still carry a germline RET mutation, so every patient gets germline RET testing. Treatment is total thyroidectomy with central neck dissection; radioiodine and TSH suppression do not work because C cells neither trap iodine nor depend on TSH. Selective RET inhibitors (selpercatinib, pralsetinib) treat advanced RET-mutant disease.

Before thyroid surgery for MTC or in any MEN2 carrier, measure plasma free metanephrines (or 24-hour urine fractionated metanephrines) and calcium. An unrecognized pheochromocytoma can cause an intraoperative hypertensive crisis; if present, it is removed first.

Prophylactic thyroidectomy. RET carriers have the thyroid removed before cancer spreads, timed by codon risk:

Functional pancreatic and duodenal NETs

Gastrinoma (Zollinger–Ellison syndrome). Most gastrinomas lie in the duodenal wall within the gastrinoma triangle, the rest in the pancreas; many are malignant and about 25% occur in MEN1. Acid hypersecretion produces multiple, recurrent, or PPI-refractory ulcers, ulcers beyond the duodenal bulb or in the jejunum, esophagitis, thick gastric folds, and diarrhea (acid inactivates pancreatic lipase). Suspect it when ulcers occur without H. pylori or NSAIDs, recur after surgery, or accompany hypercalcemia.

High gastrin with a high gastric pH is achlorhydria (PPI therapy, atrophic gastritis), not gastrinoma.

Insulinoma. The most common functional pancreatic NET is usually solitary, under 2 cm, and benign in about 90%. It causes the Whipple triad with fasting neuroglycopenia and weight gain. During hypoglycemia (glucose <55 mg/dL, often on a supervised 72-hour fast), insulin, C-peptide, and proinsulin are inappropriately high and the sulfonylurea screen is negative. Sulfonylureas reproduce this pattern apart from the positive screen, whereas exogenous insulin suppresses C-peptide. Localize with CT, MRI, or endoscopic ultrasound and enucleate; diazoxide controls unresectable disease.

Carcinoid syndrome

Mechanism. Serotonin, histamine, and kinins from a midgut NET drain to the liver and are inactivated, so the syndrome usually means hepatic metastases, or a bronchial or ovarian primary that drains straight into the systemic circulation. (The small-bowel primary itself is covered with GI neoplasms.)

• episodic flushing of the face and upper trunk
• secretory diarrhea and cramping
• wheezing from bronchospasm
• right-sided valve fibrosis: tricuspid regurgitation and pulmonic stenosis; the lungs inactivate serotonin, so left-sided lesions suggest a bronchial primary or a right-to-left shunt
• pellagra (dermatitis, diarrhea, dementia), as tryptophan is diverted to serotonin instead of niacin

Diagnosis. 24-hour urine 5-HIAA, the serotonin metabolite, comes first; avoid serotonin-rich foods (bananas, avocados, walnuts, pineapple) beforehand. Chromogranin A is nonspecific and is raised by PPIs. Ga-68 DOTATATE PET/CT stages disease, and echocardiography screens the valves.

Treatment. Octreotide or lanreotide controls flushing and diarrhea and slows tumor growth; telotristat (a tryptophan hydroxylase inhibitor) helps refractory diarrhea, and lutetium-177 DOTATATE treats progressive receptor-positive disease. Replace niacin.

Anesthesia, surgery, biopsy, or embolization can precipitate carcinoid crisis (flushing, hypotension, bronchospasm, arrhythmia). Give prophylactic octreotide before any procedure and treat a crisis with IV octreotide and fluids.

Pheochromocytoma and other syndromes

Pheochromocytoma. Episodic headache, sweating, and palpitations with paroxysmal or sustained hypertension. Confirm with metanephrines, then image the adrenals. Before adrenalectomy, give α-blockade (phenoxybenzamine or doxazosin) for 1–2 weeks with liberal salt and fluids, adding a β-blocker only afterward to avoid unopposed α-stimulation. About a third of pheochromocytomas and paragangliomas are germline, so every patient is offered genetic testing.

Von Hippel–Lindau disease. Loss of the VHL tumor suppressor stabilizes hypoxia-inducible factor. Patients develop retinal and cerebellar or spinal hemangioblastomas, multiple bilateral clear cell RCCs (the leading cause of death), norepinephrine-secreting pheochromocytomas, and pancreatic NETs and cysts. NF1 and succinate dehydrogenase (SDHx) mutations also cause pheochromocytomas and paragangliomas.