Multiple endocrine neoplasia (MEN) syndromes Flashcards
Multiple endocrine neoplasia (MEN) syndromes are autosomal dominant inherited disorders of 2 or more endocrine glands tumours
There are now 4 classified syndromes:
1. MEN type 1
2. MEN type 2A
3. MEN type 2B
4. MEN type 4 - too rare, not in PACES
MEN type 1 is due to MEN1 gene (tumour suppressor) in chromosome 11q13.
MEN1 is the commonest form of MEN, with incidence 1 in 30,000. It has very high degree of penetrance, with almost 80-98% developing features by 50 years old
It is characterised by: (3P)
1. Parathyroid tumour (hyperplasia/adenomas) as PHPT
2. Pancreatic (islet) neuroendocrine tumour (PNETs) and derivatives
3. Pituitary adenomas (anterior)
Other possible conditions:
1. Adrenal tumour
2. Carcinoid tumour
3. Lipomas
4. Angiofibromas, collagenomas
5. Meningiomas, ependymomas
MEN type 2A (95% MEN2) is due to RET proto-oncogene mutation on chromosome 10q11.2
It is characterised by: (2AddPTH)
1. Parathyroid tumour (hyperplasia/adenomas) as PHPT
2. Medullary thyroid carcinoma
3. Phaeochromocytoma (adrenal medulla)
It is associated with:
1. Cutaneous amyloidosis
2. Hirschsprung disease
MEN type 2B (5% of MEN2) is a more aggressive form with RET mutation.
It is characterised by: (2Body)
1. NO parathyroid tumour
2. Medullary thyroid carcinoma
3. Phaeochromocytoma (adrenal medulla)
Additional associations:
1. Marfanoid habitus
2. Mucocutaneous neuromas (NF)
3. Intestinal ganglioneuromatosis
4. Ocular - cornal nerve enlargement, conjunctivitis sicca
Diagnosis of MEN type 1
- Clinical: 2 or more MEN-1 tumours
- Familial: 1 MEN1-associated tumour + first-degree relative with MEN1
- Genetic: Germline MEN1 mutation, regardless of symptoms
Primary hyperparathyroidism in MEN1 results from pan-hyperplasia of all 4 glands.
- Expansion of multiple-cell clones and angiogenesis
- Commonest and earliest manifestation of MEN1 (in 90% of patients at 20-25 years old)
- Equally in men and women
Sporadic PHPT is usually single parathyroid adenoma (80-85% cases in 50-60 years old)
- More frequent in women (3:1)
Malignant transformation of pancreatic islet cells (PNETs) in MEN1 is the second commonest manifestation, occurs in 40-70% cases.
It is often complicated by early regional lymphadenopathy and liver metastases.
(making curative resection unlikely)
Functional PNETs:
1. Commonest - gastrinoma (Zollinger-Ellison)
- Excessive gastrin stimulates parietal cells and ECF-like cells causing high acid output
2. Insulinomas
- Persistent insulin secretion causes severe hypoglycaemia
3. Non-functioning PNETs (20-55%)
4. Rarely - glucagonomas, somatostatinomas, VIPomas
Gastrinomas present as multiple or refractory duodenal/jejunal ulcers with upper GI bleeding and recurrent diarrhoea.
Diagnostic investigations:
1. Gastric pH < 2
2. Serum gastrin > 300 pg/mL
3. Secretin intravenous stimulation test - post-test increase > 200pg/mL in gastrin
4. Somatostatin receptor scintigraphy, or MRI/CT abdomen
Differential diagnosis of hypergastrinaemia
- Hypercalcaemia - stimulates secretion
(including primary hyperparathyroidism) - Achlorhydria
- Gastric outlet obstruction
- Billroth II procedure
- Vagotomy
- H2 blockers or PPI
Pituitary adenomas occur in 20-50% of MEN1 either due to neoplastic transformation or excessive stimulation by ectopically produced factors by carcinoids or PNETs
Functional pituitary adenomas:
1. Commonest - prolactinoma (60%)
- Galactorrhoea, oligo/amenorrhoea, infertility and reduced libido, hypogonadism
2. GH-producing tumour (15-25%)
- Gigantism (children), acromegaly (adults)
3. Non-functioning adenomas
4. ACTH-producing tumour - Cushing’s syndrome
Management of MEN type 1
Parathyroid tumour
1. Subtotal 3.5 parathyroidectomy or total parathyroidectomy with/without graft
2. Transcervical thymectomy
(sadly recurrence rate 20-60% in MEN1 vs 4% in PHPT)
Gastrinoma
1. PPI +/- H2 blockers conservatively (most tumours too small and multiple)
2.Surgical resection if tumour > 2cm (70% develop mets)
Insulinoma
1. Endoscopic alcohol ablation
2. Surgical resection of tumours
Annual screening in symptomatic carrier of MEN1 mutation
1. Serum calcium and PTH
2. Prolactin and IGF-1
3. Gastrin
4. Glucose, insulin, glucagon, c-peptide
5. VIP and pancratic polypeptide
6. Chromogranin A
7. CT/MRI thorax and abdomen yearly
8. MRI pituitary every 3 years
Medullary thyroid carcinoma occurs in almost all cases of MEN2A and is usually the first tumour to appear.
It occurs at younger age, but has better prognosis than sporadic MTC.
Signs and symptoms:
1. Palpable thyroid nodule
2. Cervical lymphadenopathy
3. Diarrhoea and facial flushing
Treatment: total thyroidectomy +/- central node dissection
Phaeochromocytomas in MEN 2A secrete larger amounts of adrenaline compared to sporadic form.
Screening for phaeochromocytoma is mandatory before thyroidectomy
Treatment: surgical resection
+/- contralateral prophylactic resection (50% develop within 10 years of original surgery)
MEN1 vs MEN 2A vs MEN 2B
