Download multiple endocrine neoplasia

Dr. M. Sofi MD; FRCP (London); FRCPEdin;
FRCSEdin
MULTIPLE ENDOCRINE NEOPLASIA
1963 by Wermer, reported
MENsyndromes, consist of
rare, autosomal dominant
mutations in genes that
regulate cell growth.
Current classification:
 Type I & type II MEN
 Type II divided into the
type IIA & type IIB MEN
Menin protein, produced by
the MENIN gene, is a tumor
suppressor.
 Loss of this protein allows
tumors to arise.
Ret protein, produced by the
RET gene , proto-oncogene,
can be constitutively activated,
causing abnormal cell
Proliferation.
MULTIPLE ENDOCRINE NEOPLASIA
Type 1 MEN: Hyper functioning of
following tumors:
 All 4 parathyroid glands
 Pancreatic islets
◦ gastrinoma
◦ insulinoma
◦ glucagonoma
◦ vasoactive intestinal peptide
tumor (VIPoma)
◦ pancreatic polypeptide–
producing tumor (PPoma)
 Anterior pituitary
◦ prolactinoma
◦ somatotropinoma
◦ corticotropinoma
◦ nonfunctioning tumors
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Other associated tumors include:
◦ lipomas,
◦ angiofibromas
◦ located in the adrenal gland
cortex (rarely, in the adrenal
medulla).
Hyperparathyroidism is the most
common manifestation of type 1
MEN (80% of presentations)
Islet-cell tumors that secrete
predominantly gastrin are called
gastrinomas; these tumors
frequently metastasize
Pheochromocytomas are reported in
patients with type 1 MEN
Thymic and bronchial carcinoid
tumors can also be associated with
type 1 MEN
MULTIPLE ENDOCRINE NEOPLASIA
Type 2A MEN is defined by:
 Thyroid carcinoma
 Pheochromocytoma
(50%
 Hyperparathyroidism (20%)
 However Familial MTC is
hereditary MTC without other
associated endocrinopathies
 Type 2A MEN (Sipple syndrome)
accounts for most cases of type 2
MEN.
 Type 2 MEN affects about 1 in
40,000 individuals, and fewer than
1000 kindreds are known
worldwide.
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C-cell hyperplasia develops early
in life and can be viewed as the
precursor lesion for MTC, which
often arises multifocally and
bilaterally.
Pheochromocytomas are bilateral
in 70% of cases and develop on the
background of adrenomedullary
hyperplasia secondary to an RET
germline mutation.
Less than 25% of patients with type
2A MEN develop frank
hyperparathyroidism
MULTIPLE ENDOCRINE NEOPLASIA
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Bilateral
pheochromocytomas
associated with
Multiple endocrine
neoplasia type 2
MULTIPLE ENDOCRINE NEOPLASIA
Type 2B MEN is defined by:
 MTC
 Pheochromocytoma.
 Associated abnormalities
include:
◦ Mucosal neuromas
◦ Medullated corneal nerve
fibers
◦ Marfanoid habitus
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MTC is relatively aggressive and
frequently occurs in childhood
Pheochromocytomas also occur
earlier than in patients with
type 2A MEN, and patients have
the same features arising in the
context of adrenomedullary
hyperplasia, multifocality, and,
often, bilateral involvement
Carney complex
 Carney complex is a distinct, rare
type of MEN characterized by:
 Primary pigmented
adrenocortical disease,
 Pituitary adenoma,
 Sertoli-cell tumors,
 Thyroid nodules, and
 Additional nonendocrine
features.
 The most commonly associated
features are cardiac and skin
myxomas, melanotic
schwannomas, and lentigines.
Etiology
Type 1 MEN
 The MENIN gene responsible
for type 1 MEN has been
localized to chromosome band
11q13;
 It produces a nuclear protein
called menin, a tumor
suppressor.
 The MENIN gene is
ubiquitously expressed and is
localized to the nucleus of cells
 There is increasing evidence
that menin may act in DNA
repair or synthesis.
Type 2 MEN
 The genetic mutation in type 2
MEN occurs in RET protooncogene, located on band 10q11.2
 This gene defect has been
observed in both MEN2A &
MEN2B
 Activation of RET leads to
hyperplasia of target cells in vivo.
 Subsequent secondary events
then lead to tumor formation.
RET is specifically expressed in
neural crest–derived cells.
 The presence or absence of RET
expression in parathyroid tissue is
unknown
Clinical presentation
Type 1 MEN
 Hyperparathyroidism is most common initial clinical manifestation of
type 1 multiple endocrine neoplasia (MEN).
 Some patients may manifest findings of ZES before they have
hyperparathyroidism.
 Symptoms of gastrinoma may become clinically apparent either with
abdominal pain and diarrhea or with complications such as ulcer
perforation or bleeding.
Type 2A MEN
 All patients develop MTC on the basis of C-cell hyperplasia.
 About 50% of patients with MTC manifest pheochromocytomas
(usually late in life), and 20% of patients have hyperparathyroidism.
Type 2B MEN
 Pheochromocytomas occur earlier than in patients with type 2A MEN.
Clinical presentation MEN Type 1
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The age of onset of endocrine
tumors is usually in the teenage
years, but symptoms from these
tumors may not appear for several
years, and the diagnosis is
frequently delayed until the
fourth decade of life.
Cutaneous tumors may develop
prior to the manifestation of overt
clinical symptoms resulting from
endocrine tumors.
The earliest cutaneous tumors
appear in the teenage years
Hyperparathyroidism:
hypersecrete hormone causing
hypercalcaemia and recurrent
nephrolithiasis
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Zollinger-Ellison syndrome
(hypergastrinaemia)
hypoglycaemia (hyperinsulinaemia)
Prolactinoma: amenorrhoea
(hyperprolactinaemia)
Acromegaly (excess growth
hormone).
Tumors of the pituitary gland may
cause symptoms by mass effects.
Angiofibromas, collagenomas, and
lipomas do not typically cause
symptoms, and they are mostly of
cosmetic concern
Clinical presentation MEN Type 1
Parathyroid hyperplasia and
adenomas
 Hyperparathyroidism is the
presenting feature of multiple
endocrine neoplasia type 1
(MEN1) in about 80% of patients.
 Patients present either with
asymptomatic hypercalcaemia on
biochemical screening or with the
features of sporadic
hyperparathyroidism.
 All four glands are diffusely
hyperplastic and there may be
nodule formation.
Pancreatic endocrine tumors
 These occur in about 70% of
patients with MEN1.
 60% of tumors are gastrinomas and
produce ZES
 PU account for most of the MEN1
morbidity and mortality
 About 30% are insulinomas.
 VIPoma (vasoactive intestinal
peptide and pancreatic
polypeptide-secreting tumor)
 Duodenal microgastrinoma is very
common and probably accounts for
almost half of all MEN1-associated
gastrinomas.
 They are usually multiple, with up
to 15 separate tumors.
Clinical presentation MEN Type 1
Pituitary adenomas
 Present by screening in 30% of
patients, but is found at postmortem in 50%.
 Unlike the pancreas and
parathyroid, there does not
appear to be diffuse pituitary
hyperplasia.
 Prolactinoma producing
hyperprolactinaemia occurs in
about 30% of cases.
 They tend to be more aggressive
than sporadic cases.
 Acromegaly, due to excessive
human growth hormone (hGH)
occurs in about 30%.
 Adrenocorticotrophic
hormone(ACTH) may produce
Cushing's syndrome but other
functioning tumors are rare.
Skin lesions
 Occur in nearly 90% of patients,
but they can be easily overlooked.
 Benign tumors include multiple
angiofibromas, collagenomas, and
lipomas.
 They should be sought because
they can act as markers for this
syndrome.
Other lesions
 Lesions in other tissues have been
reported, but their relationship
remains controversial.
 Carcinoid tumors of the foregut,
midgut, and thymus occur in about
10%, and are often found in the
pancreas, but they are rarely
symptomatic.
Diagnosis MEN type 1
Screening of first- and
second-degree relatives of
patients with multiple
endocrine neoplasia type 1
(MEN1)
 Diagnosis of MEN1 depends on
having a high level of suspicion
in patients who present with
multiple
 Facial angiofibromas,
 Collagenomas, and lipomas
 Features hyperparathyroidism
 increased gastric acid secretion.
Investigations include:
 Hormone hypersecretion blood
tests
 Imaging studies to look for the
presence of tumors.
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DNA testing is available and
identifies a mutation in about
80% of patients with familial
MEN1.
Mutation analysis may be used
to confirm the clinical diagnosis
Screen asymptomatic family
members.
Prenatal diagnosis for
pregnancies at increased risk is
possible if the disease-causing
mutation in a family is known
Imaging features MEN Syndrome
Bilateral,
anteroposterior
radiographic views
of the hands in a
patient with type 1
(MEN1) and primary
hyperparathyroidis
m. These images
show subperiosteal
bone resorption
along the radial
aspects of the
middle phalanges.
Imaging features MEN Syndrome
Computed tomography (CT) scan
of the pancreas in a patient with
multiple endocrine neoplasia
syndrome type 1 (MEN1) and a
gastrinoma. This image shows
a pancreatic head mass (large,
white arrow), as well as a lowattenuating lesion in the liver
(small, black arrowhead) that
indicates metastases.
Calcifications of the right renal
medullary pyramids (medullary
nephrocalcinosis; black
arrows) in this nonenhanced CT
scan.
Imaging features MEN Syndrome
Computed
tomography (CT)
scan image with oral
and intravenous
contrast in a patient
with biochemical
evidence of
insulinoma. The 3cm contrastenhancing
neoplasm (arrow) is
seen in the tail of
the pancreas (P)
posterior to the
stomach (S)
Imaging features MEN Syndrome
6x5x5 cm adrenal mass arising from right adrenal
Screening tests MEN type 1
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The screening of first- and
second-degree relatives of
patients with (MEN1) is aimed at
early detection of parathyroid,
pancreatic or pituitary lesions in
gene carriers, to reduce the
associated morbidity.
There is no evidence that
screening reduces mortality
Identification of affected
individuals in 'malignant kindred'
with aggressive pancreatic disease
may allow curative surgery which
would be expected to prolong
survival.
Screening lowers the age of
detection of the syndrome by
about 20 years.
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Screening tests are serum calcium,
fasting gastrin, and prolactin.
Sensitive markers of pancreatic
disease are basal and test-meal
stimulated pancreatic polypeptide
and gastrin, and basal insulin and
proinsulin.
80% of affected individuals will
have been identified by the 5th
decade.
Screening of sporadic pancreatic
endocrine tumors for evidence of
MEN1 is probably justified,
especially for gastrinomas or
insulinomas.
There is little evidence to support
screening in those with sporadic
pituitary tumors.
Management
If the condition is confirmed,
then genetic counseling is
required
Pharmacological
 Diazoxide can be used to
inhibit release of insulin,
especially in tumors that are
beyond surgery.
 High-dose proton pump
inhibitors are required for
gastrin-secreting tumors.
 After surgery to the pituitary,
hormone replacement may be
required
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Surgical
 Skin tumors may be removed
 The surgical approach to
pancreatic endocrine tumors in
MEN1 is controversial:
◦ Surgical cure is best achieved by
removing the pancreas and
duodenum with adjacent lymph
nodes. There is still a high rate of
recurrence but the overall
mortality remains low
 Pituitary tumors: Same as for
sporadic pituitary tumors.
 Parathyroidectomy, subtotal or
complete, is practiced for MEN1 but
long-term follow-up reveals a high
rate of recurrence in MEN1.
 The treatment of metastatic disease
is the same as in sporadic cases.
Prognosis MEN type 1
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The average age of death in individuals with multiple
endocrine neoplasia type 1 (MEN1) is significantly lower
(55.4 years for men and 46.8 years for women) than
that of the general population.
Pancreatic endocrine tumors, particularly gastrinomas,
become malignant in about 50% of patients with MEN1.
Untreated, patients may die from peptic ulcer disease,
metastatic endocrine pancreatic carcinoma, or foregut
carcinoid malignancy.
Pancreatic endocrine tumors associated with MEN1 are
less malignant than sporadic tumors and carry a better
prognosis, with a median survival of 15 years compared to
5 years for patients with sporadic tumors.
This may reflect more indolent disease or earlier diagnosis.
Clinical presentation MEN Type 2A
Patients may present with
symptoms related to:
◦ Medullary thyroid carcinoma
◦ Hyperparathyroidism
◦ Pheochromocytoma.
Virtually all patients have MCT
symptoms may include:
◦ hypertension
◦ episodic sweating
◦ diarrhoea
◦ pruritic skin lesions
◦ lump in the neck(which may
cause compressive
symptoms).
Hypercalcaemia may lead to:
◦ constipation,
◦ polyuria,
◦ polydipsia,
◦ memory problems
◦ depression,
◦ nephrolithiasis,
◦ glucose intolerance,
◦ gastro-oesophageal reflux, and
◦ fatigue
Chronic constipation.
Cutaneous lichen amyloidosis in
multiple endocrine neoplasia type
2A (MEN2A) presents with
 multiple pruritic, hyperpigmented,
lichenoid papules in the scapular
area of the back.
Cutaneous lichen amyloidosis
Clinical presentation MEN Type 2B
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Present earlier than MEN2A.
Neuromas usually predate MTC
and phaeochromocytoma.
Almost all patients have a
Marfan's-like habitus.
Neuromas appear as:
◦ Glistening bumps around the
lips, tongue, and lining of the
mouth.
◦ Bumps on the eyelids, which are
often thickened - neuromas may
also appear on the cornea and
conjunctiva.
Intestinal ganglioneuromatosis
affects about 75% of cases.
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Neuromas involve the autonomic
nerves of both the myenteric and
submucosal plexi and can cause
poor suckling, with failure to thrive,
constipation, diarrhea, recurrent
pseudo-obstruction, toxic
megacolon.
Patients also often develop spinal
abnormalities. These features, along
with thickened lips and eyelids are
associated with Marfanoid
habitus.
Involvement of peripheral motor
and sensory nerves can cause a
peroneal muscular atrophy
(Charcot-Marie-Tooth syndrome)
Delayed puberty is a common
feature.
MULTIPLE ENDOCRINE NEOPLASIA
Mucosal neuromas
Diagnosis of multiple endocrine neoplasia type 2
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Screening for pheochromocytoma is
24 hours urine for elevated
catecholamines and catecholamine
metabolites, especially vanillylmandelic acid (VMA).
Clinical suspicion or elevated
urinary catecholamine values
demand an abdominal MRI scan. A
metaiodobenzylguanidine (MIBG)
scan is useful for localizing
pheochromocytomas
Thyroid tumors can be investigated
initially by ultrasound and fineneedle aspiration.
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Medullary thyroid carcinoma
(MTC) is suspected with an
elevated plasma calcitonin
concentration.
This is a specific and sensitive
marker.
In provocative testing, calcitonin
concentration is measured before
and 2 and 5 minutes after
intravenous administration of
calcium.
Parathyroid abnormalities are
diagnosed when there are
simultaneously elevated serum
calcium and parathyroid hormone
levels with an elevated urinary
calcium to creatinine ratio.
Screening for multiple endocrine neoplasia type 2
The two types of molecular
diagnosis for MEN2 are mutation
analysis and linkage analysis of
the RET proto-oncogene
(chromosomal locus 10q11)
 Genetic linkage analysis has 9899% predictive accuracy
Screening, to identify affected
individuals and for early detection
of thyroid, parathyroid and
adrenal disease, reduces both
morbidity and mortality in MEN2:
 Annual 24-hour urine collections
for catecholamine concentrations
to detect pheochromocytoma at
the earliest age possible.
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Recurrence of medullary thyroid
carcinoma (MTC) should be
monitored with
◦ Calcitonin
◦ Carcinoembryonic antigen
(CEA)
◦ Provocative calcitonin testing
with the pentagastrin
stimulation test, with serial
measurements of serum
calcitonin measured.
False-positive and false-negative
results have been reported
Management MEN type 2
General principles
 In type 2 (MEN2) the goals are:
 Identify individuals with germline
RET-disease-causing mutations
associated with MEN2 before
symptoms develop.
 Reduce morbidity and mortality
in the highest-risk individuals
through either:
 Prophylactic thyroidectomy
 Screening for medullary thyroid
carcinoma (MTC)
 Screening phaeochromocytoma
and parathyroid disease before
symptoms develop.
 Counseling of patients with MEN
that they know what to expect
and why continued follow-up
MEN2A
 The treatment for adrenal
medullary hyperplasia or
phaeochromocytoma is bilateral
adrenalectomy.
 If an adrenal lesion is identified at
the same time as MTC, the
adrenalectomy performed first.
 Total thyroidectomy as young as 3
years for MEN2A if they contain the
genetic mutation.
 Hyperparathyroidism: subtotal
parathyroidectomy is advised,
along with cervical thymectomy
because of the increased risk of
supernumerary parathyroid glands.
 Recurrent hyperparathyroidism is
less likely to occur in MEN2A
patients than in MEN1 patients
Management MEN type 2B
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In MEN 2B, thyroidectomy with
lymph node clearance should be
performed at the earliest possible
age.
MTC is biologically aggressive in
these patients and has been
reported as early as 15/12 age, with
metastases by the age of 3 years.
Patients with the genetic mutation
for MEN2B, total thyroidectomy is
recommended in infancy.
Patients not identified by screening,
thyroidectomy should still be
performed.
In all patients with palpable tumors,
central lymph node dissection
should also be performed.
Useful markers in the follow-up of
MTC are plasma calcitonin and
carcinoembryonic antigen (CEA).
Prognosis
 Patients with MEN2B tend to do
worse than those with MEN2A, as
the MTC is more aggressive.
 The prognosis is poor in this group,
with recurrent disease in about 20%
of patients with clinically occult but
macroscopic MTC
 Over 60% with palpable MTC.
 It is particularly poor in individuals
with MEN2B who present with
clinically apparent MTC.
 Their 10-year survival is about 50%,
and death from metastatic disease
in the mid-twenties is common
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Medullary cell carcinoma of the thyroid
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Initial thyroid lesion in MEN2 is Ccell hyperplasia, which has been
found as early as the age of 3 years
in MEN2A and may be present at
birth in MEN2B.
Over 5 to 10 years microscopic MTC
develops and finally gross tumors
become apparent.
MTC typically presents as a neck
mass at about age 15 to 20 years.
More than 50% already have
cervical lymph node metastases.
MTC may occur alone without other
features of MEN2.
MTC is a tumor of the C cells which
secrete calcitonin, and this acts as a
tumor marker
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Inherited MTC accounts for 25% of
cases in association with MEN types
2A and 2B
It may present with a thyroid lump
diarrhea may also occur.
Metastases may occur, to the lung,
liver and bone.
Paraneoplastic syndromes are rare
Cushing's or carcinoid may occur
Investigations include ultrasound
scan, calcitonin levels, FNA, and
DNA testing for familial cases.
Adverse prognostic indicators
include older age, higher-grade
lesions and incomplete surgical
resection of the lesion
Pheochromocytoma
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Phaeochromocytoma occurs
in 50% of MEN2.
In patients with MEN2 are
usually found in the adrenals
About 70% are bilateral,
almost all are benign.
Produce excessive adrenaline
secretion leading to
tachycardia, palpitations,
hypertension and headache.
Investigations include plasma
concentrations of free
metanephrines, and CT or
MRI
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Positron emission
tomography (PET) is also
used for diagnosis.
Treatment surgical,
laparoscopic surgery is
increasingly used.
Overall, half of the patients
with malignant
pheochromocytomas
remain alive for five years.