Multiple endocrine neoplasia

Question 1

Define multiple endocrine neoplasia syndrome. What tumours does it include?

Answer 1

Hereditary tumour syndromes with distinct patterns of organ involvement and characterised by the development of multiple endocrine tumours.

Question 2

What are the types of MEN syndrome? What genes are involved?

Answer 2

• MEN1 - 80-90% caused by MEN1 which encodes menin 1, gene mutations on chr 11q
• MEN2 - RET proto-oncogene mutations are responsible for almost all cases - menin 2 gene located on Chr 10q
  
  • MEN2A
  • MEN2B
  • Familial medullary thyroid cancer

Mutations in different codons can confer different risks of aggressiveness and penetrance.

Question 3

How is MEN1 diagnosed?

Answer 3

Based on having 2 or more of the MEN-1 associated tumours or 1 tumours and a first-degree relative with the condition.

OR on the basis of genentics alone with shown mutation in MEN1

Question 4

What are the MEN1 tumours?

Answer 4

MEN1: the number “1” in MEN1 should remind you of primary or prime number. MEN1 involves things that start with the letter P:

• Pituitary adenoma
• Parathyroid hyperplasia
• Pancreatic islet cell tumors (gastrinoma, insulinoma, glucagonoma)

Question 5

What tumour is common to MEN1 and MEN2A?

Answer 5

Parathyroid hyperplasia

Question 6

What tumour is common to MEN2A and MEN2B?

Answer 6

Medullary carcinoma of thyroid

Question 7

What are the MEN2 tumours?

Answer 7

MEN2A: happens to involve the letter C (This is MEN2A, so there are two C’s in each item!):

• Calcitonin (thyroid medullary carcinoma with elevated calcitonin level)
• Calcium (parathyroid hyperplasia, which causes elevated calcium levels)
• Catecholamines which are made in the chromocytes (as in pheochromocytoma)

Men 2B: B is for big (marfanoid habitus) and for belly problems (mucosal neuromas)

Question 8

Which MEN syndrome presents with mucosal neuromas on the lips, tongue and eyelids?

Answer 8

MEN2B

Note that Abraham Lincoln was said (apocryphally?) to have been marfanoid, and he clearly was one of the great “men to be” (MEN2B)!

Question 9

Which non-endocrine tumours is MEN1 associated with ?

Answer 9

• Cutaneous tumours
• Lipomas
• Facial angiofibromas

Question 10

Which MEN syndrome is associated with

1. CNS tumours e.g. meningiomas?
2. Hirschsprung’s disease?
3. Cutaneous lichen amyloidosis?
4. isolated medullary cancers and no other MEN2 manifestations?
5. facial angiofibromas?

Answer 10

1. MEN1
2. MEN2A
3. MEN2A
4. familial medullary thyroid cancer (MEN2)
5. MEN1 (non-endocrine)

Question 11

What is the clinical presentation of MEN1?

Answer 11

Hypercalcemia: brittle bones (fractures, due to osteoporosis), kidney stones, abdominal moans (abdominal pain), and psychiatric overtones (confusion).

Treatment-resistant peptic ulcer disease (gastrinoma) or hypoglycemia (insulinoma).

Question 12

What is the clinical presentation of MEN2A?

Answer 12

Hypercalcemia: brittle bones (fractures, due to osteoporosis), kidney stones, abdominal moans (abdominal pain), and psychiatric overtones (confusion).

Elevated catecholamines: severe, treatment-resistent hypertension (particularly paroxysmal in nature, with headaches, palpitations, and diaphoresis).

Question 13

What is the clinical presentation of MEN2B?

Answer 13

• Marfanoid habitus
• Mucosal neuromas on lips, tongue and eyelids.

Question 14

What investigations would you do for MEN syndrome ?

Answer 14

Genetic testing = debatable in MEN1 as high false-negative rate; test for RET protooncogene in MEN2

Other:

• Serum calcium - in MEN1 and 2A
• Prolactin, IGF1, pituitary hormones - in pituitary adenoma
• Serum chromogranin A, proinsulin, pancreatic polypeptide, vasointestinal peptide, gastrin, and glucagon (fasting gut peptides) - measure annually in MEN1, help early detection
• Fasting serum glucose/insulin levels - in MEN1 with neuroglycopenic symptoms
• Gastrin levels - elevated in gastrinoma, H pylori or PPI use
• Calcitonin - measures disease burden in medullary cancer
• Plasma metanephrines or total catecholamines in 24hr urine collection - screens for phaeochromocytoma in MEN2
• 72hr fasting test - for insulinoma

Imaging:

• Octerotide scans - good for foregut and pancreas tumours
• 18F-DOPA PET - for phaeochromocytoma
• Endoscopy - for gastrinomas; do H pylori test first to rule out before gastrinoma.

Invasive:

• FNA - for thyroid nodules; stain for calcitonin

Question 15

What screening is available for patients witn MEN1?

Answer 15

Screening:

• every 3 years for adenomas with pituitary MRI,
• every year for pancreatic masses and
• every 3 years for adrenal masses with abdominal CT or MRI,
• every 1 to 2 years for thymic or bronchopulmonary masses with chest CT or MRI

Question 16

What is the management of MEN syndromes?

Answer 16

Prophylactic thyroidectomy - if high risk mutations, may be done at <5yrs old.

Hyperparathyroidism

• Hydration - at least 3L a day for those with hyperparathyroidism related hypercalcaemia +/- bisphosphonates
• Subtotal parathyroidectomy

Zollinger Ellison/gastrinoma

• Surgery - duodeno-pancreatectomy (Whipple procedure)
• PPI

Pancreatic lesion

• Octreotide - somatostatin analogue, since somatostatins expressed widely in NETs
• Surgery - Whipple’s

Pituitary adenoma

• Observation
• Surgery - if mass effect or compressed optic chiasm

Prolactinoma

• Dopamine agonists - bromocriptine

ACTH/GH producing tumour

• Surgery - transsphenoidal

Medullary thyroid cancer

• Total thyroidectomy +/- lymph node dissection
• If inoperable: symptom control with loperamide (for diarrhoea)
• If metastatic: tracheal stenting - prevents tracheal compression

Phaeochromocytoma

• Alpha-blocker e.g. phenoxybenzamine
• Beta-blockade e.g. propranolol
• Long term hydrocortisone and fludrocortisone
• Surgery - adrenalectomy, may be bilateral

Question 17

What is the prognosis with MEN syndromes?

Answer 17

Neuroendocrine tumours can recur as new clonal tumours, meaning lifelong monitoring is required even for patients who have undergone successful surgery.