MEN Syndromes Pathology
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Direct answer
Three genes anchor the multiple endocrine neoplasia (MEN) map: MEN1 (menin, chromosome 11q13) producing the "3 Ps" — parathyroid hyperplasia, enteropancreatic neuroendocrine tumours and pituitary adenomas; RET (10q11.2) in MEN2A, adding medullary thyroid carcinoma, pheochromocytoma and parathyroid disease; and the same RET gene at codon 918 in MEN2B, where mucosal neuromas and a marfanoid habitus replace the parathyroid component. All are autosomal dominant, but their management differs radically: MEN1 is a surveillance programme of biochemical screening, while MEN2 is a surgical-prevention programme, because prophylactic thyroidectomy in childhood — timed to the RET codon risk category — removes the medullary carcinoma that is otherwise virtually inevitable. Operate the pheochromocytoma before the thyroid, always, or the catecholamine surge of thyroid surgery kills the patient.
What you must remember
- MEN1 (Wermer): primary hyperparathyroidism in over 90 per cent (four-gland hyperplasia), enteropancreatic tumours in roughly 40 to 60 per cent — gastrinoma the commonest functioning tumour (Zollinger-Ellison syndrome), then insulinoma — and pituitary adenomas in about a third, prolactinoma leading; also foregut carcinoids and adrenal tumours.
- MEN1 screening panel: calcium and parathyroid hormone yearly, plus prolactin, insulin-like growth factor 1, and gastrin or chromogranin A — a quotable annual set, with imaging at intervals; penetrance is near-complete by later life.
- MEN2A (Sipple): medullary thyroid carcinoma in virtually 100 per cent (bilateral, multifocal, preceded by C-cell hyperplasia), pheochromocytoma in about 50 per cent (bilateral in half), parathyroid hyperplasia in 20 to 30 per cent; cutaneous lichen amyloidosis is a recognised marker.
- MEN2B: the earliest and most aggressive medullary carcinoma, pheochromocytoma, mucosal neuromas of lips and tongue, marfanoid habitus and gastrointestinal ganglioneuromatosis causing constipation — with no parathyroid disease, the negative that examiners love.
- RET risk categories drive surgery timing (per American Thyroid Association guidance): MEN2B (codon 918, highest risk) — thyroidectomy within the first year of life; MEN2A codon 634 — by around age five; lower-risk codons later, with calcitonin surveillance.
- Sequencing rule: in a MEN2 patient with both pheochromocytoma and medullary carcinoma, the adrenal is dealt with first after alpha-blockade, because uncontrolled catecholamine release under thyroid-surgery anaesthesia is lethal.
- Calcitonin as marker: basal and stimulated calcitonin track C-cell disease; the precursor lesion is diffuse C-cell hyperplasia, more than a specified number of C cells per follicle — histology examiners accept as the definition.
How cascade screening actually runs
Consider a 28-year-old whose father died of metastatic medullary thyroid carcinoma. The index step is RET sequencing of the affected relative or, failing that, of the proband; a codon-634 mutation confirms MEN2A. Every first-degree relative then offers a blood sample, not a calcitonin level — genetic testing precedes biochemical testing because C-cell disease begins before calcitonin rises reliably. A positive nine-year-old cousin undergoes calcitonin measurement and thyroidectomy timed to the risk category; a positive 45-year-old aunt additionally needs annual plasma metanephrines and calcium. Each operated thyroid is examined for C-cell hyperplasia and microcarcinoma, and each patient — even after apparently curative surgery — remains on lifelong calcitonin and carcinoembryonic antigen surveillance for recurrence.
MEN1 cascade runs on biochemistry rather than prophylactic surgery: the parathyroids are hyperplastic and recurrent, pancreatic tumours are multiple and often duodenal (gastrinomas in the duodenal submucosa are small and easily missed — a surgical aphorism worth quoting), and pituitary disease is monitored with hormone profiles and imaging. The two syndromes thus teach opposite philosophies: RET is a gene you act on surgically; MEN1 is a gene you watch.
Where the exam sets its traps
Candidates routinely blur the direction of the MEN2A-thyroid relationship: virtually all MEN2A patients develop medullary carcinoma, but only a minority of sporadic medullary carcinomas are heritable — hence RET testing is now offered to every medullary carcinoma patient, not only the familial ones. The second trap is the MEN2B face: the child with mucosal neuromas and constipation from ganglioneuromatosis goes undiagnosed for years; recognising the phenotype at a viva desk is precisely the point. Third, do not transplant MEN1 habits into MEN2: prophylactic pancreatectomy is never done; prophylactic thyroidectomy always is, at the codon-appropriate age.
Frequently asked questions
Which three organs define MEN1 and which tumour is commonest?
Parathyroids (hyperplasia, over 90 per cent), enteropancreatic neuroendocrine tumours and pituitary adenomas; primary hyperparathyroidism is the commonest and usually first manifestation.
What distinguishes MEN2B from MEN2A?
MEN2B adds mucosal neuromas, marfanoid habitus and gut ganglioneuromatosis, has earlier and more aggressive medullary carcinoma, and lacks parathyroid hyperplasia.
Why is prophylactic thyroidectomy performed in RET mutation carriers?
Medullary carcinoma is virtually inevitable and radioiodine-insensitive, so removing the thyroid at a codon-determined age — in infancy for MEN2B — prevents incurable disease.
Which tumour is operated first when pheochromocytoma and medullary carcinoma coexist?
The pheochromocytoma, after alpha-blockade, so that thyroid surgery is not complicated by an intraoperative catecholamine crisis.
What is the precursor lesion of medullary thyroid carcinoma in MEN2?
Diffuse and nodular C-cell hyperplasia — multifocal bilateral expansion of calcitonin-secreting parafollicular cells preceding invasive carcinoma.