Topic review

Multiple Endocrine Neoplasia (MEN)

NARUENONT DOLSARITCHAIYA,
MD.

Today's scopes

Definition and classification

Clinical manifestation
Screening
Treatment

Definition
MEN : a disorder with neoplasms in two
or more different hormonal tissues in
several members of a family (a)
Several genetics disorders predispose
to endocrine gland neoplasia e.g. MEN
syndrome, VHL syndrome, NF , Carney
complex
(a) Harrison's principle of internal medicine, 18th edition

Classification
MEN 1
MEN 2

MEN 1

MEN 1 or Wermers syndrome

Inherited as autosomal dominant
Most common MEN syndrome
Consisting of neoplasia of
1. parathyroid glands
2. enteropancreatic tumors
3. anterior pituitary adenomas
4. other neuroendocrine tumors with
variable
penetrance

MEN 1
Genetics
Inactivating mutations of tumorsuppressor gene MEN1 located at
chromosome 11q13
MEN1 gene encodes a protein
Menin
Menin suppresses the JunDdependent transcriptional activation

MEN 1

MEN 1
Clinical manifestation
Primary hyperparathyroidism
Most common and earliest manifestation
Hypercalcemia usually develops around
age of 40 or early during teenage years
Cardinal features of MEN 1
multicentricity
Clinical manifestations are similar to
those of sporadic hyperparathyroidism

MEN 1
Clinical manifestation
Primary hyperparathyroidism
Differentiation from other forms of
familial primary hyperparathyroidism is
based on family history,
histopathology, MEN1 gene mutation
and observation of features of
MEN 1
Parathyroid hyperplasia is the most
common

MEN 1
Clinical manifestation
Enteropancreatic tumors
Second most common manifestation of
MEN 1
Occur in parallel with
hyperparathyroidism
Most tumors secrete peptide hormones
which cause specific syndrome
Insidious onset, silent tumors
Metastasis to liver is common

MEN 1
Gastrinoma
Most common enteropancreatic tumor
Excessive gastrin production from
small carcinoid-like tumor in
duodenum or less often by pancreatic
islet cell tumors
Zollinger-Ellison syndrome :
esophagitis, multiple duodenal ulcers
and diarrhea

MEN 1
Gastrinoma
Diagnosis by increased gastric acid
secretion, elevated basal gastrin level ( >
115 pmol/L) and exaggerated response of
serum gastrin to either secretin or calcium
CT, MRI, octreotide scan and/or
endoscopic ultrasound aid in localizing
primary and metastatic tumor
Intraoperative ultrasound is the most
sensitive

MEN 1
Insulinoma
Second most common
enteropancreatic tumors of MEN 1
Mostly originate in pancreas, can be
benign or malignant
Secreting excessive amount of insulin
which cause hypoglycemia

MEN 1
Insulinoma
Diagnosis by documenting
hypoglycemia during fasting with
inappropriate elevation of serum
insulin and C-peptide levels
Large insulinomas can be detected by
CT or MRI but small ones need
endoscopic ultrasound or
intraoperative ultrasound

MEN 1
Glucagonoma
Syndrome of hyperglycemia,
necrolytic migratory erythema skin
rash, anorexia, glossitis ,anemia,
depression, diarrhea and venous
thrombosis
Glucagonoma syndrome
Some patients also have elevated
plasma ghrelin level

MEN 1

necrolytic migratory erythema

MEN 1
VIPoma
Verner-Morrison syndrome or
pancreatic cholera
Overproduction of vasoactive
intestinal peptide (VIP)
Voluminous diarrhea with
hypokalemia, hypochlorhydia and
metabolic acidosis

MEN 1
Clinical manifestation
Enteropancreatic tumors
About one-third is malignant with liver
metastasis
Screening is very important to early
detection and prompt treatment

MEN 1
Clinical manifestation
Enteropancreatic tumors
Annual screening of individuals at risk
with measurement of basal and mealstimulated levels of pancreatic
polypeptide hormone
Surgical removal of early stage islet cell
tumor is curative
Measurement of polypeptide hormones
every 2-3 years is another approach

MEN 1
Clinical manifestation
Pituitary tumors
Occur in 20-30% in MEN 1 and tend to be
multicentric
Can exhibit aggressive behavior and local
invasiveness
Prolactinomas are most common and
diagnosed by serum prolactin level > 200
ug/L with or without pituitary mass by MRI

MEN 1
Clinical manifestation
Pituitary tumors
Acromegaly is the second most common
pituitary tumor in MEN 1
Interestingly, acromegaly can be rarely
caused by production of GHRH by islet cell
tumor
Cushings disease is caused by ACTHproducing pituitary tumor or ectopic ACTH
production from islet cell or carcinoid tumor

MEN 1
Clinical manifestation
Other tumors
Adrenocortical tumors are found in about
one-half of gene carriers but rarely
functional
Rare cases of pheochromocytoma has
been documented
Carcinoid tumors causing carcinoid
syndrome are late manifestation of MEN 1

MEN 1
Clinical manifestation
Other tumors
Subcutaneous or visceral lipomas and
cutaneous leiomyoma may be present
Skin angiofibromas and collagenomas
are seen in most with MEN 1

MEN 1
Genetic considerations
MEN1 gene mutations are found in >
90% of families with the syndrome
Genetic testing can be performed in
individual at risk
Routine screening for individuals
carrying mutant gene should be
performed

MEN 1
Treatment : hyperparathyroidism
Indication for parathyroid exploration
- serum calcium > 12 mg/dL
- evidence of calcium nephrolithiasis
- renal dysfunction
- neuropathic or muscular symptoms
- osteopenia
- age < 50

MEN 1
Treatment : hyperparathyroidism
Two approaches of parathyroid surgery
1) All parathyroid tissue is removed
with
re-implantation in the
non-dominant forearm
2) Removal of 3-3.5 parathyroid
glands with carefully marking the
location of residual tissue

MEN 1
Treatment : pancreatic islet cell tumors
Multicentricity and diabetes mellitus from
total pancreactomy complicate
management
General valid concepts
1) tumors producing insulin, glucagon, VIP,
GHRH or CRH should be resected
2) tumors producing gastrin are preferably
treated by PPIs because of multicentricity
and frequent liver metastasis

MEN 1
Treatment : pancreatic islet cell tumors
Management of metastatic disease is
unsatisfactory
Medical treatment include PPIs for ZES
and somatostatin analogues for carcinoid,
glucagonoma and VIPoma syndrome
Liver metastasis can be treated with
TACE, RFA or chemotherapy to slow
progression but never curative

MEN 1
Treatment : pituitary tumors
Prolactinoma responds very well with
dopamine agonists (bromocriptine
e.g.)
Transphenoidal resection is the
mainstay treatment for acromegaly
and Cushings disease

MEN 2
Medullary thyroid carcinoma (MTC)
and pheochromocytoma are
associated in these syndromes
Inherited as autosomal dominant
Two major syndromes : MEN 2A and
MEN 2B

MEN 2
There are 3 subvariants of MEN 2A
1) Familial medullary thyroid carcinoma
2) MEN 2A with cutaneous lichen
amyloidosis
3) MEN 2A with Hirschprung disease
MEN 2B consists of MTC,
pheochromocytoma, mucosal neuromas,
intestinal ganglioneuromatosis and
marfanoid features

MEN 2

Cutaneous lichen

MEN 2A
Clinical manifestation
Medullary thyroid carcinoma
MTC is the most common manifestation
Usually develops in childhood
Typically located at the junction of the
upper one-third and lower two-thirds of
each lobe of thyroid gland
Diagnosis by measuring serum calcitonin
level after calcium or pentagastrin
injection

MEN 2A
Clinical manifestation
Pheochromocytoma
Occur about 50% in MEN 2A
Half are bilateral and > 50%
undergone unilateral adrenalectomy
develop pheochromocytoma in the
contralateral gland within decade

MEN 2A
Clinical manifestation
Pheochromocytoma
Disproportionate increase in secretion
of epinephrine relative to
norepinephrine which distinguishes
MEN 2 from sporadic
pheochromocytoma and those
associated with VHL, NF and
hereditary paraganglioma

MEN 2A
Clinical manifestation
Hyperparathyroidism
Occur in 15-20% of patients
Similar clinical symptoms and signs to
other forms of hyperparathyroidism
Multiglandular parathyroid hyperplasia
is the most common histologic finding

MEN 2A
Clinical manifestation
Subvariant of MEN 2A
Familial MTC is the most common
MTC is the only manifestation of FMTC
Establish diagnosis by identification of
MTC in multiple generations without
pheochromocytoma
Diagnosis of FMTC should be carefully
made because pheochromocytoma is 50%
penetrant

MEN 2B
Clinical manifestation
MTC, pheochromocytoma, mucosal
neuromas and marfanoid habitus
designate MEN 2B
MTC in MEN 2B develops earlier and is
more aggressive than in MEN 2A
Pheochromocytoma occurs in more
than half in MEN 2B

MEN 2B
Mucosal neuroma are
present on the tip
of the
tongue,
under eyelids and
throughout GI tract
They are true
neuromas which are
distinct from
neurofibroma

MEN 2B

MEN 2B
Genetic considerations
RET proto-oncogene have been identified
in most patients with MEN 2
RET proto-oncogene is located on the
proximal arm of chromosome 10q
(10q11.2)
Genetic testing for RET proto-oncogene
should be performed on an individual with
proven MEN 2A and each family member
at risk (tested twice for more accuracy)

MEN 2B
Genetic considerations
Genetic testing for RET proto-oncogene
should be performed in patients with
suspected MEN 2B and also family at risk
Annual screening for
pheochromocytoma in patients with RET
mutations by measuring basal plasma or
24-hr urine catecholamines and
metanephrines is recommended

MEN 2B
Treatment : MTC
Total thyroidectomy with central lymph
node dissection should be carried out in
children with mutant gene with excellent
outcome in long-term follow-up
Total thyroidectomy with central lymph
node dissection and selective dissection
of other regional chains provide the best
chance for cure

MEN 2B
Treatment : MTC
Radiation for extensive local
metastasis to reduce tumor size or
prevent local recurrence
Chemotherapy for palliation

MEN 2B
Treatment : pheochromocytoma
Q : Remove both adrenal glands or
only the affected one ?
Possibility of malignancy versus risks
of adrenal insufficiency
Most clinicians recommend removing
only the affect gland
Alternative approach is corticalsparing adrenalectomy

MEN 2B
Treatment : hyperparathyroidism
Similar to MEN 2 approaches