Multiple Endocrine Neoplasia
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Direct answer
RET germline mutations turned hereditary endocrine cancer into a preventable disease: in MEN2A and MEN2B, knowing the mutation allows prophylactic thyroidectomy before medullary carcinoma ever develops — in the first year of life for MEN2B, by around age five for MEN2A. MEN1 (menin, chromosome 11q13, autosomal dominant) is the classic triad of parathyroid hyperplasia (the commonest and usually first manifestation, above 90 per cent), pancreatic endocrine tumours (about 60 per cent, gastrinoma leading to Zollinger-Ellison) and pituitary adenomas (prolactinoma commonest). MEN2A (RET) pairs medullary thyroid carcinoma with phaeochromocytoma (roughly half) and parathyroid hyperplasia (a minority); MEN2B adds mucosal neuromas, marfanoid habitus and gut ganglioneuromatosis, drops the parathyroid component, and produces the earliest, most aggressive medullary carcinomas from C-cell hyperplasia.
What you must remember
- MEN1 gene and triad: menin tumour suppressor on 11q13; parathyroid hyperplasia (commonest, multiglandular, causes hypercalcaemia), enteropancreatic endocrine tumours (gastrinoma — Zollinger-Ellison with recurrent/multiple peptic ulcers and diarrhoea; insulinoma; others), and pituitary adenomas (prolactinoma leading) — plus cutaneous angiofibromas and collagenomas as stigmata.
- MEN2A (Sipple syndrome): RET proto-oncogene (10q11.2); medullary thyroid carcinoma with virtually complete penetrance, bilateral and multifocal, arising on C-cell hyperplasia; phaeochromocytoma in about half (bilateral in half of those); parathyroid hyperplasia in a minority; cutaneous lichen amyloidosis described.
- MEN2B: the Met918Thr RET mutation in the vast majority; the most aggressive MTC, often in infancy; phaeochromocytoma; mucosal neuromas on tongue and lips, thickened corneal nerves (a slit-lamp clue), marfanoid habitus without lens dislocation, and intestinal ganglioneuromatosis causing constipation; parathyroid disease characteristically absent.
- MTC markers: calcitonin (screening and follow-up), CEA for advanced disease, amyloid within tumour stroma, and calcitonin-positive, chromogranin-positive C cells on immunohistochemistry.
- Management sequence for MEN2: RET testing at birth (MEN2B) or in early childhood (MEN2A), prophylactic total thyroidectomy based on mutation risk class, annual biochemical screening for phaeochromocytoma (metanephrines) before any thyroid surgery, and parathyroid assessment — operating on an unrecognised phaeochromocytoma risks a hypertensive crisis — the most-tested safety point.
- Screening package for MEN1 kindreds: calcium and PTH from adolescence, prolactin and IGF-1, fasting gastrin and insulin, plus menin sequencing for the family — the exam expects the "which test, which age" reasoning.
- Indian context: MEN is under-diagnosed in India because family screening is incomplete; any medullary thyroid carcinoma, or phaeochromocytoma with hypercalcaemia or prolactin-related amenorrhoea, warrants a syndromic workup rather than isolated tumour treatment.
Screening a MEN family
Start with the index case. A 34-year-old with a thyroid nodule shows amyloid-rich medullary carcinoma with calcitonin staining; RET testing reveals a MEN2A codon 634 mutation. Every first-degree relative is now offered targeted RET testing. A nephew testing positive gets baseline calcitonin and thyroid ultrasound, and prophylactic total thyroidectomy around age five, because the mutated RET drives C-cell hyperplasia into multifocal carcinoma with near-certainty; the excised gland in a well-timed prophylactic specimen may show only C-cell hyperplasia — the goal. Before any surgery in an adult carrier, screen plasma or urinary metanephrines: a bilateral adrenal medullary tumour must be removed first or covered with alpha-blockade. Post-thyroidectomy, lifelong calcium and vitamin D (if parathyroids were autotransplanted or devascularised), calcitonin surveillance for recurrence, and continued annual phaeochromocytoma screening complete the protocol. Contrast the MEN1 index case — a 28-year-old with recurrent duodenal ulcers and a gastrinoma: screen calcium and PTH (hyperparathyroidism is usually the first and easiest manifestation), prolactin, and pancreatic imaging; genetic testing of relatives follows, and hypercalcaemia correction precedes gastrinoma surgery, since hypercalcaemia worsens gastrin release.
How the exam frames it
Three question formats recur. One-liners test associations: hypercalcaemia plus prolactinoma — MEN1; medullary carcinoma plus phaeochromocytoma — MEN2A; mucosal neuromas plus constipation from birth — MEN2B. Case vignettes test sequencing: a MEN2 patient needs phaeochromocytoma exclusion before thyroidectomy (the safety point), and a MEN1 gastrinoma patient needs parathyroid evaluation first. Negative-association questions are the trap tier: parathyroid involvement is absent in MEN2B — attaching hyperparathyroidism to all MEN loses easy marks; MEN2 is driven by an activating oncogene (RET), not tumour-suppressor loss like MEN1. The histology favourite is C-cell hyperplasia as the precursor lesion, and the IHC favourite is calcitonin positivity. Finally, know the age logic: MEN2B thyroidectomy within the first year, MEN2A around five years, MEN1 screening from adolescence — numbers examiners quote back at you.
Frequently asked questions
What are the three classical components of MEN1?
Parathyroid hyperplasia causing hypercalcaemia, enteropancreatic endocrine tumours (gastrinoma commonest), and pituitary adenomas (prolactinoma commonest), from menin loss on 11q13.
Which gene and mutation underlie MEN2A and MEN2B?
Both involve the RET proto-oncogene on 10q11.2 — MEN2A classically codon 634, MEN2B the Met918Thr mutation — with medullary thyroid carcinoma as the penetrant core tumour.
Why is prophylactic thyroidectomy performed earlier in MEN2B than MEN2A?
MEN2B medullary carcinoma arises in infancy and behaves aggressively, so thyroidectomy is recommended within the first year of life, whereas MEN2A tumours emerge later, permitting surgery around age five.
What must be excluded before thyroidectomy in a MEN2 patient?
Phaeochromocytoma, by plasma or urinary metanephrines — unrecognised catecholamine excess can precipitate intraoperative hypertensive crisis.
Which histological lesion precedes medullary thyroid carcinoma in MEN2?
C-cell hyperplasia — diffuse expansion of calcitonin-producing parafollicular cells, the precursor from which multifocal bilateral carcinomas develop.