Download MULTIPLE ENDOCRINE NEOPLASIA Type 1 MEN

MULTIPLE ENDOCRINE
NEOPLASIA
Dr. M. Sofi MD; FRCP (London);
FRCPEdin; FRCSEdin
MULTIPLE ENDOCRINE NEOPLASIA
Multiple endocrine neoplasia
(MEN) syndromes consist
of rare, autosomal
dominant mutations in
genes that regulate cell
growth.
Classification recognizes:
• Type I & type II MEN
•
Type II divided into the
 Type IIA
 Type IIB
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 is hyperfunctioning 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
MULTIPLE ENDOCRINE NEOPLASIA
Type 2A MEN is defined by:
• Thyroid carcinoma (100%)
• Pheochromocytoma (50%)
• Hyperparathyroidism (20%)
• 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
• C-cell hyperplasia
develops early in life and
can be viewed as the
precursor lesion for MTC,
which often arises
multifocally and bilaterally.
• Less than 25% of patients
with type 2A MEN develop
hyperparathyroidism
• Pheochromocytomas are
bilateral in 70% of cases and
develop on the background
of adrenomedullary
hyperplasia secondary to an
RET germline mutation.
MULTIPLE ENDOCRINE NEOPLASIA
Type 2B MEN is defined by:
• MTC
• Pheochromocytoma.
• Associated abnormalities include:
– Mucosal neuromas
– Medullated corneal nerve fibers
– Marfanoid habitus
• 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
Etiology
Type 1 MEN
Type 2 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 RET gene is responsible
for type 2 MEN protooncogene, located on band
10q11.2
• RET leads to hyperplasia of
target cells in vivo and
tumor development
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
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
post-mortem 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.
Diagnosis MEN type 1
• Screening of first- and
second-degree relatives type
1 (MEN1)
• Diagnosis of MEN1 depends
on high level of suspicion in
patients with multiple
• Facial angiofibromas,
• Collagenomas, and lipomas
• Features of
hyperparathyroidism
• High gastric acid secretion.
Investigations include:
• Hormone hypersecretion
• Imaging studies for the
presence of tumors.
• 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
Radiographic views
of the hands in a
patient with type 1
(MEN1) and primary
hyperparathyroidism.
These images show
sub-periosteal bone
resorption along the
radial aspects of the
middle phalanges.
Sub-periosteal resorption as well as acroosteolysis,
the next sign of hyperparathyroidism
Imaging features Type 1 MEN Syndrome
CT scan of the pancreas in a
patient with type 1 (MEN1)
and a gastrinoma. Image
shows a pancreatic head mass
(large, white arrow), as well as
a low-attenuating 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 Type 1 MEN Syndrome
CT scan image with
oral and intravenous
contrast in a patient
with biochemical
evidence of
insulinoma.
The 3-cm contrastenhancing neoplasm
(arrow) is seen in the
tail of the pancreas
(P) posterior to the
stomach (S)
Imaging features Type 1 MEN Syndrome
6x5x5 cm adrenal mass arising from right adrenal
Screening tests MEN type 1
• Screening tests are:
 Serum calcium,
 Gasting gastrin,
 Prolactin.
• Sensitive markers of pancreatic disease are basal and testmeal 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
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
• 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.
MCT symptoms may include:
 Lump at the base of the neck(which may cause
compressive symptoms).
 Hoarseness, dysphagia, and respiratory difficulty
 Diarrhea secondary to high plasma calcitonin levels
 Although uncommon, paraneoplastic syndromes,
including Cushing or carcinoid syndrome
 Distant metastases (eg, lung, liver, bone) may result in
weight loss, lethargy, and bone pain
Clinical presentation MEN Type 2A
25% of MEN Type 2A have
Hperparathyroidism and
associated hypercalcemia
may lead to:
 Polyuria
 Polydipsia
 Constipation
 Memory problems
 Depression,
 Nephrolithiasis
Cutaneous lichen amyloidosis in
multiple endocrine neoplasia type 2A
(MEN2A) presents with multiple
pruritic, hyperpigmented, lichenoid
papules in the scapular area of the back.
Clinical presentation MEN Type 2B
Patients may present with symptoms related to:
– Medullary thyroid carcinoma
– Pheochromocytoma.
– Neuromas usually predate MTC and pheochromocytoma.
• Almost all patients have a Marfan's-like habitus.
• Neuromas appear as:
– Glistening bumps around the lips, tongue, and mouth.
– Bumps on the eyelids, which are often thickened
• Involvement of peripheral motor and sensory nerves can
cause a peroneal muscular atrophy (Charcot-Marie-Tooth
syndrome)
 Intestinal ganglioneuromatosis affects about 75% of cases.
• Delayed puberty is a common feature.
MULTIPLE ENDOCRINE NEOPLASIA
Mucosal neuromas
Diagnosis of multiple endocrine neoplasia type 2
• Screening for pheochromocytoma is 24 hours urine for
elevated catecholamines and catecholamine metabolites,
especially vanillyl-mandelic acid (VMA).
• Clinical suspicion or elevated urinary catecholamine
values demand an abdominal MRI scan. A
metaiodobenzylguanidine (MIBG) scan is useful for
localizing pheochromocytomas.
• Thyroid tumours can be investigated initially by
ultrasound and fine-needle aspiration.
Diagnosis of multiple endocrine neoplasia type 2
• 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 and
Linkage analysis
of the RET proto-oncogene
(chromosomal locus 10q11)
• Genetic linkage analysis has
98-99% predictive accuracy
• Screening for early
detection of thyroid,
parathyroid and adrenal
disease, reduces both
morbidity and mortality in
MEN2:
• Recurrence of medullary
thyroid carcinoma (MTC)
should be monitored with
– Calcitonin
– Carcinoembryonic
antigen (CEA)
• False-positive and falsenegative results have been
reported
Management MEN type 2
General principles
• Identify individuals with
germline RET-diseasecausing mutations
associated with MEN2
before symptoms develop.
• Reduce morbidity and
mortality in the highest-risk
• Prophylactic thyroidectomy
• Screening for MTC
• Phaeochromocytoma
screening and parathyroid
disease before symptoms
develop.
• Counseling of patients with
MEN
• The treatment for adrenal
medullary hyperplasia or
phaeochromocytoma is
bilateral adrenalectomy.
• Total thyroidectomy for
patients 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.
Management MEN type 2B
• 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.
• Patients with the genetic
mutation for MEN2B, total
thyroidectomy is
recommended in infancy.
• Patients not identified by
screening, thyroidectomy
should still be performed.
Prognosis
• Patients with MEN2B tend
to do worse than those with
MEN2A
• It is particularly poor in
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
Medullary Thyroid carcinoma
• Initial thyroid lesion in
MEN2 is C-cell hyperplasia,
which has been found as
early as the age of 3 years in
MEN2A and may be present
at birth in MEN2B.
• Over the subsequent 5 to 10
years microscopic MTC
develops and finally gross
tumors become apparent.
• MTC typically presents as a
neck mass or neck pain at
about age 15 to 20 years.
• More than 50% already have
cervical lymph node
metastases.
• Inherited MTC accounts for
25% of cases in association
with MEN types 2A and 2B,
but non-MEN familial MTC
also occurs.
• It may present with a
thyroid lump. Diarrhoea
may also occur.
• Metastases may occur, to the
lung, liver and bone.
• Paraneoplastic syndromes
are rare but may include
Cushing's or carcinoid
syndrome.
Pheochromocytoma
• Phaeochromocytoma occurs
in 50% of MEN2.
• In patients with MEN2 are
usually found in the
adrenals
• About 70% are bilateral,
almost all are benign.
• They produce excessive
adrenaline secretion leading
to tachycardia, palpitations,
hypertension and headache.
• Investigations include
plasma concentrations of
free metanephrines, and
imaging CT or MRI
• 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.