Multiple Endocrine Neoplasia

MEN-1

Familial cases show autosomal dominant transmission. 70% of clear familial cases show mutations in MEN1 (menin=tumour suppressive gene), though lower in sporadic MEN1. MEN1 cases found in around 10% of familial primary hyperparathyroidism. Cyclin-dependent kinase inhibitor (CDKI) mutations (p15,p18,p21,p27) are also found in a small number of MEN1 cases.

Tumours (italics = neoplastic potential):

  • Parathyroid adenoma (95%)
  • Pancreatic tumour (70%)
    • gastrinoma (40%)
    • insulinoma (10%)
    • non-functioning including PPP-oma (20%)
    • other (glucagon, VIP, somatostatin) - <2%
  • Pituitary (40%)
    • prolactinoma (25%)
    • non-functioning (10%)
    • GH (5%)
    • ACTH (2%)
  • Non-functioning foregut-derived carcinoids
    • thymic (2%)
    • bronchial (4%)
    • gastric (10%)
  • Adrenal
    • non-functioning (30%)
    • cortical functioning or cancer (2%)
    • phaeochromocytoma
  • Hyperparathyroidism mean age is 30 years earlier than in non-MEN. Parathyroidectomy may reduce gastrin levels, so some recommend early parathyroidectomy.
  • Gastrinoma presents with acid hypersecretion: peptic ulcer disease, GORD, reflux. Nodal metastasis is common; hepatic metastasis (in 20%) has poor survival. Medical therapy (PPI) is very effective. Surgery has a near-zero cure rate.
  • Glucagonoma: hyperglycaemia, anorexia, anaemia, diarrhoea, necrolytic migratory erythema. Octreotide may help. Insulinoma: usually solitary, so surgery often effective. VIP-oma: watery diarrhoea, hypokalaemic hypochloraemic acidosis. Foregut-derived carcinoids generally do not hypersecrete. Tend to present later than other MEN tumours.
  • Screening in known MEN-1 carriers. Annual…
    • Parathyroid – Ca, PTH
    • Gastrinoma – gastrin, secretin-stimulated gastrin
    • Insulinoma – fasting glucose, C-peptide
    • Other pancreatic – chromogranin, Octreoscan or pancreatic MRI
    • Pituitary – prolactin, IGF-1
    • Carcinoid – chromogranin

MEN-2

Autosomal dominant inheritance of RET oncogene.

MEN-2A

30% of MEN-2A carriers never have significant disease.

  • Medullary thyroid cancer (100%) - MEN accounts for about 25% of MTC.
    • MTC cells may express TRH, gastrin-releasing peptide, VIP, but these are not normally clinically important
    • 5% secrete ACTH, which may result in Cushing’s syndrome
    • Total thyroidectomy is mandatory
    • Monitoring is by calcitonin levels +/- pentagastrin stimulation.
  • Phaeochromocytoma (50%)
    • Phaeochromocytoma is rarely malignant in MEN-2A - medical management alone has been increasingly used
    • MTC should prompt surveillance for phaeochromocytoma and parathyroid disorders in patients and relatives
    • Penetrance of phaeo in MEN-2A is lower than MTC, so MEN-2A may be mistaken for FMTC
  • Parathyroid hyperplasia/tumours (25%)
    • MTC should prompt surveillance for parathyroid disorders in patients and relatives

Variants

  • Familial medullary thyroid carcinoma (FMTC)
  • MEN-2A plus cutaneous lichen amyloidosis
  • MEN-2A or FMTC plus Hirchsprung’s disease

MEN-2B

  • MEN-2B is MEN-2A with mucosal neuromas, and sometimes Marfanoid habitus, pectus excavatum, slipped femoral epiphyses
  • MTC is much more aggressive in MEN-2B than in other forms
  • Familial or sporadic mutations of the RET proto-oncogene are identified in all cases
  • RET combines with GFRα-1 to form a complex which ‘entices’ neurons into developing organs in the embryo, hence the association with Hirchsprung’s disease
  • Mucosal neuromas are characteristically present on the distal tongue, lips, subconjunctivae and throughout the GI tract
  • Ganglioneuromatosis of the GI tract can cause obstruction or diarrhoea, or may be noted by chance during abdominal surgery
  • The pentagastrin stimulation test may be used for tumour surveillance and carrier assessment, although DNA testing for RET is likely to dominate
  • All people with a known RET mutation should be recommended total thyroidectomy

Von Hippel-Lindau Syndrome

  • Autosomal dominant with 90% penetrance of:
    • Haemangioblastomas of CNS
    • Retinal angiomas
    • Renal cell carcinomas
    • Visceral cysts
    • Phaeochromocytomas (30%)
    • Islet cell tumours
  • Most have CNS tumours. VHL protein degrades hypoxia-inducible factor 1, so VHL syndrome would seem to be the result of uncontrolled angiogenesis.

Neurofibromatosis type 1

Associated phaeochromocytoma, hyperparathyroidism, midgut tumours and hypothalamic tumours.