MEN

1
MEN

• Nitin Malhotra

2
Multiple Endocrine Neoplasia

• MEN Type 1
• Wermers Syndrome
• MEN Type 2A
• Sipples Syndrome
• MEN Type 2B

3
MEN Type 1

• Defined as the presence of two of the three main
  MEN1 tumor types
• Parathyroid Adenoma
• Pancreatic Endocrine Adenoma
• Pituitary Adenoma

4
Parathyroid Adenoma

• 1 Hyperparathyroidism
• Most common manifestation of MEN1
• 100 penetrance by age 40-50
• Mean onset at 25 years of age
• Seen 2 decades earlier than in sporadic
  hyperparathyroidism

5
1 Hyperparathyroidism SXStones, Bones,
abdominal moans, and psychiatric overtones

• Constitutional / Neuropsych complaints
• Weakness, fatique, irritability, depression
• Urinary tract findings
• Urolithiasis, Hypercalciuria
• Abdominal Pain
• Peptic ulcer disease, pancreatitis
• Bone disease
• Decreased bone density, bone pain, fractures
• Asymptomatic hypercalcemia

6
(No Transcript)
7
Diagnosis

• Hypercalcemia WITH inappropriately high serum PTH
  concentrations
• Hypophosphatemia
• Hypercalciuria
• Classic Radiologic findings
• Osteopenia and bone demineralization are present
  in all forms of hyperparathyroidism
• Subperiosteal resorption is virtually
  pathognomonic for hyperparathyroidism and is
  typically seen at the radial aspect of the middle
  phalanx of the index and middle fingers

8
(No Transcript)
9

• Sporadic 1 hyperparathyroidism
• Female predominance
• Fourth to sixth decade of life
• 80-85 have single parathyroid adenomas
• Low rate of recurrence (lt5)

• MEN1 1 hyperparathyroidism
• Male to female ratio equal
• Second to fourth decade of life
• Multicentricity or multiple gland involvement
• High rate of recurrent hyperparathyroidism s/p
  successful parathyroidectomy (gt50)
• Neoplastic genetic stimulus not eliminated

10
Pancreatic Islet Cell Adenoma / GI Adenomas

• 2nd most common manifestation of MEN1
• Present at autopsy in 80 of MEN 1 patients
• Less often diagnosed during life clinically
  apparent in 1/3 of patients
• MALIGNANT potential 1/3 have malignant features
  including hepatic metastases
• direct correlation between tumor size and rate of
  metastases
• Primary life-threatening manifestation of MEN1

11
Pancreatic Islet Neoplasia

• Increased hormonal production
• Pancreatic polypeptide (PP)
• Most common type, but non-functional
• Gastrin
• Most common type of functional tumor
• Insulin
• VIP
• Glucagon
• Somatostatin
• Rarely ACTH, CRH, GHRH

12
Gastrinoma

• Present in 40 of MEN-1 patients
• Causes Zollinger-Ellison syndrome
• Hypersecretion of Gastrin gt hypersecretion of
  gastric acid
• Severe peptic ulcer disease refractive to
  conservative therapy
• Secretory diarrhea
• Esophagitis

13
Gastrinoma Dx

• Fasting serum gastrin gt 100pg/ml
• Basal acid output gt 15mEq/hr
• If above tests are equivocal
• IV secretin challenge showing exaggerated serum
  gastrin response
• Gastrin level increases gt 200pg/ml
• Secretin inhibits gastrin release from G cells
  and increases bicarb secretion
• Note Hypercalcemia can exacerbate ZES and
  further elevating serum gastrin concentrations

14
Insulinoma

• SX
• Neuroglycopenic symptoms (drowsiness, seizures,
  coma)
• Adrenergic symptoms
• Weight gain (patients minimize sx by eating
  frequently)
• DX via supervised fast for 72 hours
• Neuroglycopenic symptoms
• Serum glucose lt 45
• Serum insulin greater than 5µU/mL
• Elevated blood C-peptide and proinsulin levels

15
Glucagonoma

• Sx
• Hyperglycemia
• Necrolytic migratory erythema
• Anorexia
• Glossitis
• Anemia
• Depression
• Diarrhea
• Venous thrombosis
• Dx elevated plasma glucagon levels

16
Non-biochemical Dx

• Localization with CT and endoscopic u/s most
  helpful
• Octreotide radionuclide scan
• Octreotide uptake depends on tumor density of
  type 2 somatostatin receptors
• Angiography
• Tumors identified during arteriography as
  vascular blush
• Provactive angiography
• Secretin (for gastrinoma) or Calcium (for
  gastrinoma or insulinoma) selectively injected
  into regional arteries
• Hepatic venous hormone output is subsequently
  measured

17
Pituitary Adenomas

• Clinically apparent develop in 15-20 of MEN1
  patients
• Pathological prevalence may be over 60
• MEN1 pituitary adenomas compared to non-MEN1
  patients show
• LARGER and MORE AGGRESSIVE tumors
• Difficult to resect

18
Prolactinoma

• Most common type of pituitary tumor
• Sx
• Irregular menses
• Galactorrhea
• Infertility
• Impotence
• Dx
• MRI or CT scan of the sella turcica
• Serum prolactin gt200µg/L with or without mass
  appreciated by MRI
• Visual field examination

19
Other types of Pituitary Adenomas

• Growth hormone-producing acromegaly
• Second most common
• ACTH producing Cushings syndrome
• Non-functioning tumors

20
Genetics of MEN1

• Autosomal dominant disorder Mutation in TSG on
  11q that encodes the protein menin
• Genetic testing available
• Major value is for assignment or exclusion of
  gene carrier status
• If carrier requires routine screening (starting
  at 20-30 y/o) for individual MEN1 manifestations
  (Ca, prolactin, fasting glucose/insulin, gastrin)
• If negative despite family history no further
  screening required
• Little evidence that early, presymptomatic
  detection reduces MM

21
MEN 2A

• Medullary Thyroid Cancer (MTC)
• Pheochromoctyoma
• 1 Parathyroid hyperplasia
• ...3 X more common than MEN 2B

22
MTC

• Most common manifestation
• Nearly all patients develop clinically apparent
  MTC, usually developing in childhood
• Begins as hyperplasia of calcitonin-producing
  cells (C-cells or parafollicular cells)
• Calcitonin inhibits osteoclast mediated bone
  resorption
• However, its physiologic role in humans in
  unknown, it is thought to regulate blood calcium
  when levels are high
• Multicentric hyperplasia of the parafollicular C
  cells is the hallmark of MEN2

23
MTC

• Sx 1 or more firm nodules, which are often
  associated with enlarged cervical lymph nodes
• Responsible for deaths in MEN2A
• patients should undergo total thyroidectomy
  before age 6
• Distant Mets lung, liver, bone

24
MTC

• Dx
• Elevated serum calcitonin concentrations
• Correlate with size of tumor
• May be normal in small tumors or in those with C
  cell hyperplasia
• Calcium stimulation test
• Rapid infusion of Calcium Gluconate to fasting pt
• Serum calcitonin measured at baseline and at 2
  and 5 minutes after stimulation
• Positive if peak conc after stimulation is 3X
  basal conc or gt300ng/L

25
Pheochromocytoma

• Seen in almost 50 of patients with MEN2A
• Seen 10 years after C-cell hyperplasia/MTC
• Sx paroxysms of HTN, palpitations, nervousness,
  HA, diaphoresis, and tachycardia
• Distinctive qualities
• Almost always in adrenal glands
• Very rarely malignant, mets uncommon
• 50 bilateral
• gt50 develop pheo in contralateral gland s/p
  unilateral adrenalectomy

26
Pheo

• Dx
• 24 hr urine collection for total catecholamines,
  vanillylmandelic acid, and metanephrines
• Localize with CT
• MUST BE DX AND REMOVED before thyroid or
  parathyroid surgery
• Requires preoperative treatment for 7-10d with
  phenoxybenzamine

27
1 hyperparathyroidism

• Occurs in 15-20 of patients
• Symptoms less severe than that in MEN1
• Dx same as in MEN1

28
MEN 2B

• MTC more aggressive than MEN2A, distant mets
  reported as early as 1st year of life
• Pheochromocytoma
• NO hyperparathyroidism
• Characteristic Phenotype
• Marfanoid habitus (no ectopia lentis or aortic
  abnormalities)
• Puffy lips and bumpy tongue mucosal neuromas
• Hyperflexible joints
• Ganglioneuromas
• Often located in intestines/colon gt severe
  constipation and megacolon

29
Serious this time
30
Genetics of MEN 2A/B

• Autosomal Dominant disorder
• Mutation of RET proto-oncogene Chr 10
• Screening of at-risk family is ESSENTIAL
• Mandates therapeutic intervention (MTC)
• Family should be genotyped and searched for the
  RET mutation found in affected individual
• Negative RET no further screening
• Positive RET ppx thyroidectomy and further
  screening
• Screen at birth or soon after