MEN syndromes

The Multiple Endocrine Neoplasia syndromes occur as a result of a genetic change leading to the development of both benign and malignant tumours in endocrine organs and tissues

MEN1

Genetics
- Autosomal dominant - phenotypic carriers are heterozygotes - I presume homozygote embryos are non-viable
- Germline, loss-of-function mutation in the MEN1 tumour suppressor gene on 11q13
  - Menin (the protein produced by this gene) is involved in control of G1 to S phase cell cycle progression
  - A 'second hit' is still required - if the other normal copy of the allele is damaged in a cell, loss of function can result, leading to cell proliferation and eventual neoplastic transformation
- 1 in 30,000 in general
- 1-18% of patients with primary hyperparathyroidism have it
- 3% of patients with pituitary adenomas have it
- Commercial testing available since around 1990. 10-20% will not have an identifiable mutation by conventional testing. Genetic testing can't be used to predict clinical course at this time.
Presentation: the three p's
- Typically has become evident by age 29
- Hyperparathyroidism from parathyroid adenomas/hyperplasia - almost all develop primary HPT by 50yo, and are most likely to develop multigland disease
  - 95% penetrance, usually the first manifestation
  - Diagnose biochemically, usually around 20yo
  - Usually have multiglandular disease
  - Affected parathyroids are typically benign
  - Sestamibi is useful to identify ectopic glands prior to exploration
- Microadenoma of anterior pituitary
  - Penetrance 15-50%, typically occurring age 20-40
  - Symptoms either from hormone secretion (prolactin, growth hormone, corticotropin) or local effects of the tumour resulting in visual field defects
- Pancreatic NET
  - Penetrance 30-80%
  - Can be functional or non-functional - gastrinoma (50%), insulinoma, VIPoma
  - Chromogranin A or pancreatic polypeptide can be useful as markers even if non-functional
  - Screen biochemically with imaging for further investigation
    - See separate topic under 'pancreas' for more detail on workup
  - 90% of gastrinomas in MEN1 are malignant, and >50% have lymph node metastases. Very good prognosis for isolated tumours, but 52% at five years for those with liver mets.
- Also (less commonly)
  - Adrenocortical and thyroid tumours
  - NET of thymus (most dangerous), bronchus and stomach
    - Preventative trans-cervical thymectomy no longer recommended
  - Meningioma
  - Facial angiofibroma
  - Collagenomas
  - Multiple lipomas
  - Breast cancer
  - PUD as a complicated of ZES is common
Diagnosis
- Positive to genetic testing
- Two MEN1-associated tumours
- One MEN1-associated tumour and a first-degree relative with MEN1
Management
- Primary hyperparathyroidism has two treatment options, both reasonable options; however ultimate recurrence is assured if patients are followed long enough
  - Subtotal (3.5) parathyroidectomy
    - Gives less post-op hypocalcaemia, but 20-30% have recurrent or persistent hypercalcaemia within 10 years
    - 26-45% have hypoparathyroidism
  - Total parathyroidectomy with auto-transplantation into a location outside the neck, typically brachioradialis
    - Recurrence rates 4-20%
    - Hypo-parathyroid rates 40-60%
  - Patients with recurrence and no surgical options can be treated with calcimimetics
  - Don't need pre-op localisation studies
- Enteropancreatic NETs
  - Surgical management is aimed at controlling hormone excess, preventing metastatic progression, and preventing local invasion
  - Manage as per recommendations for sporadic PNETs - see separate topics
- Pituitary adenomas
  - Treat as for sporadic adenomas
Screening (offer to anyone with either genetic or clinical diagnosis)
- Pituitary
  - 10+: annual clinical review and prolactin/IGF-1
  - 20+: add MRI every 4 years
- Parathyroid
  - 10+: annual calcium, phosphate, vit D and PTH
- PNET
  - 15+: annual hormonal testing
  - 20+: MRI every two years
- Thymus
  - 20+: MRI every two years
- ACC
  - 20+: MRI every two years
- Bronchopulmonary NET
  - 30+: chest imaging every two years
Genetic testing indications
- Index patients with suspected MEN1
- First-degree relatives
- Can be offered to asymptomatic relatives
Prognosis
- Disease-specific survival of 88% at 30 years, mean age at death 50-55 years

MEN2

Genetics
- First described in 1960s
- Gain-of-function germline mutation in the RET (REarranged during Transfection) proto-oncogene on 10q11.2
- Autosomal dominant
- Codes for a membrane receptor with tyrosine kinase activity which is present in thyroid parafollicular cells, parathyroid glands, enteric ganglia, adrenal chromaffin cells, and peripheral and central neurons
- Distinct genotype-phenotype correlation depending on specific type of RET gene inherited; thus treatment depends on genetic testing
- Prevalence 1 in 35,000
Diagnosis
- Confirmed RET mutation
- Clinical diagnosis can be made in families with the syndrome but no identifiable RET mutation
- Offer screening to anyone with MTC, 2 or more typical cancers, or first-degree relatives. Typically do it in infancy.
MEN2A (most common subtype)
- Note Familial MTC which is considered to be an entity within MEN2A, but without potential for other cancers - rely on history of familial MTCs but no other cancers in family. MTC usually develops in mid-40s.
- Presentation:
  - Medullary thyroid cancer >90%
    - Hallmark feature
    - Can be multifocal
    - Usually develops in mid-20s
    - 10-year survival 94%
  - Phaeochromocytoma 40-50%
    - Tends to be benign (95%)
  - Primary HPT - penetrance 15-35%.
    - Single adenoma or diffuse hyperplasia.
    - Management approach similar to sporadic hyperparathyroidism
  - Adrenal medullary hyperplasia
  - Cutaneous lichen amyloidosis - repeated scratching leads to amyloid deposition in dermis
  - Hirschsprung disease
  - Normal physical appearance and body habitus
MEN2B
- Presentation
  - MTC
    - Hallmark
    - Develops as early as infancy
    - Tends to be aggressive with early metastases
    - 10-year survival 60%
  - Phaeochromocytomas (50%)
  - Mucosal neuromas of lips and tongue
  - Ganglioneuromatosis of the GIT
    - Oesophageal dysmotility
    - Abdominal bloating
    - Intermittent constipation
    - Diarrhoea
  - Marfanoid appearance - elongated facies, Marfinoid habitus, everted eyelids, ophthalmologic abnormalities, skeletal abnormalities including pectus excavatum and scoliosis
  - Adrenal medullary hyperplasia
Management
- Screen for phaeo before doing anything - 34% of patients with MTC have phaeo
- Prophylactic thyroidectomy recommended in infants/children/adolescents depending on specific mutation present (see table below)
  - ATA-MOD: start screening at 5yo with 6-12-monthly calcitonin, and use that to determine when to operate
  - ATA-H: operate at 5yo, or earlier if serum calcitonin dictates otherwise
- MTC
  - Total thyroidectomy with central node dissection if localised to neck
  - Require yearly calcitonin for life to detect recurrence
  - Recurrence
    - Re-operate if limited to neck
    - RAI, CTX, RTX are not useful
    - Vandetanib can initiate partial or complete response - tyrosine kinase inhibitor - used for metastatic disease
- Phaeochromocytoma
  - A cortical-sparing or partial adrenalectomy is preferred when possible because of the high likelihood of future contralateral disease
- Hyperparathyroidism
  - Explore and remove abnormal-appearing glands, using pre-operative imaging to guide exploration
Screening
- MTC
  - Thyroidectomy, not screened
- Phaeochromocytoma:
  - Annual screening (BP and bloods) starting at age 11, or age 16 for ATA-MOD risk
- Parathyroid (MEN2A only):
  - Annual PTH and serum calcium starting at age 11 or 16 depending on risk

MEN4

Rare inherited syndrome
Clinically similar to MEN1 - may account for people meeting clinical criteria for MEN1 without a known MEN1 mutation
CDKN1B gene mutation
Management recommendations
- If primary HPT - subtotal parathyroidectomy and transcervical thymectomy