MULTIPLE ENDOCRINE NEOPLASIA

DR DINA EL GAYAR
PROFESSOR OF CHEMICAL PATHOLOGY
CAIRO UNIVERSITY
Definition

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Multipleendocrine neoplasia syndrome is defined as
a disorder with neoplasms in two or more different
hormonal tissues in several members of a family.

Threewell-defined MEN syndromes MEN 1, MEN 2,

MEN 3 and MEN 4
 MEN1 (Wermer's syndrome)

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It is inherited as an autosomal dominant trait.
Although rare, MEN1 is the most common MEN syndrome
with prevalence of 220 per 100,000 .
Reported age range of 581 years
 MEN1 GENE
On chromosome 11q13
Consists of 10 exons that span 9 kb and encode a 610 amino acid protein called MENIN
Mutations: Germline & Somatic
Menin acts as a tumor suppressor, involved in cell functions such as copying and
repairing DNA and regulating the activity of other genes.
When mutations inactivate both copies of the MEN1 gene, Menin is no longer available
to control cell growth and division. It occurs in selected endocrine tissues leading to the
classic MEN1 phenotype
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 The syndrome is characterized by:

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1. Hyperparathyroid 95% due to hyperplasia of the four glands
2. Enteropancreatic tumors 50% of patients functional or non funcional
3. Anterior pituitary adenomas 20-25%,
4. Adrenal adenomas 30%
5. Thyroid nodules 10%
Hyperparathyroid
The first manifestation of MEN TYPE 1
85% of patients Hyperparathyroid
15% of patients insulinoma or a prolactinoma

Approximately 2% of patients with newly diagnosed primary

hyperparathyroidism will have underlying MEN1.

The mean age is significantly younger in MEN1 than in sporadic states.

Thus apparent sporadic primary hyperparathyroidism in young patients

should prompt consideration of an underlying diagnosis of MEN1.

MEN1-associated parathyroid carcinoma is extremely rare.

Enteropancreatic tumors

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Second most common manifestation of MEN1,
30% are malignant
Estimated penetrance of 50%.
They tend to occur in parallel with hyperparathyroidism.
Tumors secrete peptide hormones that cause specific clinical
syndromes.
A. Gastrinomas

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Most common enteropancreatic tumors in MEN1 patients
Result in the Zollinger-Ellison syndrome (ZES).
The robust acid production may cause; Esophagitis, Duodenal
ulcers throughout the duodenum, Ulcers (which is commonly
refractory to conservative therapy such as antacids) and Diarrhea.
Occurs in > of MEN1 pts with small carcinoid-like tumors in
the duodenal wall or, less often, by pancreatic islet cell tumors.
There may be > one gastrin-producing tumor, making localization
difficult.
 Diagnosis

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Elevated basal gastrin levels in the serum [generally >115 pmol/L

An exaggerated response of serum gastrin to either secretin or

calcium to differentiate from other causes of elevated Gastrin
(treatment with H2 receptor antagonists or proton pump inhibitors,
achlorhydria)
CT MRI
Localization Techniques Endoscopic and intraoperative US: ,
selective arterial secretin injection followed by vein sampling for
Gastrin.
B.Insulinomas

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Second most common enteropancreatic tumors in MEN
Diagnosis
Hypoglycemia after a short fast
Inappropriate elevation of serum insulin and C-peptide
levels.
Large insulinomas may be identified by CT or MRI
scanning.
Intraoperative ultrasonography. Selective hepatic vein
sampling for insulin
C . Glucagonoma

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seen occasionally in MEN1,
a syndrome of , hyperglycemia, skin rash ( necrolytic migratory
erythema),anorexia, glossitis, anemia, depression
glucagon level is double fold elevated
D.VIPomas
(1%) secrete VIP and cause profuse watery diarrhea,
hypokalemia, and achlorhydria

E. Somatostatinomas (0.7%) can cause diabetes

mellitus, steatorrhea, and cholelithiasis.
 Pituitary tumors
occur in 2030% of patients

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These tumors can exhibit aggressive behavior and local invasiveness
that makes them difficult to resect.
1 Prolactinomas
Most common
serum prolactin levels >200 g/L
serum prolactin levels <200 g/L may be due to a prolactin-secreting
neoplasm or to compression of the pituitary stalk by a different type of
pituitary tumor.
2 Acromegaly
due to excessive GH production is the second most common syndrome
caused by pituitary tumors in MEN1.
.

3. Cushing's disease:
It is caused by

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ACTH-producing pituitary tumors
or
Ectopic production of ACTH or CRH(islet cell or
carcinoid tumors or adrenal adenomas).

Pituitary Cushing's disease is diagnosed by a high-dose

dexamethasone suppression test or by petrosal
venous sinus sampling for ACTH after IV injection of
CRH.
Adrenal adenomas /hyperplasia

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in about 37% of patients with MEN 1

50% are bilateral.

They are generally benign and nonfunctional.

These adrenal lesions are pituitary independent

 Basis for a diagnosis of MEN1
(by one of three criteriae)

CLINICAL FAMILIAL GENETIC

A patient with 2 or more A patient with 1 MEN1- An individual who has an MEN1
MEN1- associated tumours associated tumour and mutation but does not have clinical
a first degree relative or biochemical manifestations of

with MEN1 MEN1 i.e. a mutant gene carrier

Genetic testing
MEN1 germline mutation testing should be offered to :
Patients with MEN1 or an index case with two or more MEN1-associated endocrine tumors

MEN1 germline mutation testing may be recommended in individuals with an atypical MEN1
phenotype

Their first-degree relatives (asymptomatic or who have clinical manifestations of MEN1) as

manifestations may occur by the age of 5 yr.

Individuals who are found to have a MEN1 germline mutation should be screened regularly (e.g. on an
annual basis) for development of MEN1-associated tumors.

If a coding region MEN1 mutation is not identified, then testing for partial or whole-gene deletion, or
haplotype analysis of the MEN1 locus, or analysis of other genes should be considered

N.B.
Relatives of a patient with a known MEN1 mutation should be offered MEN1 germline mutation analysis
before biochemical and radiological screening tests for the detection of MEN1 tumors, so as to avoid the
burden of undergoing multiple tests involving different modalities and to reduce financial costs .
 MEN Type 2(Sipple's Syndrome)

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It is inherited as an autosomal dominant trait.
prevalence of 1-10 per 100,000 .
The International RET Mutation Consortium has proposed three
phenotypic subtypes of MEN-2
MEN-2 (1) MTC, pheochromocytoma, and hyperparathyroidism
MEN-2 (2) MTC and pheochromocytoma
MEN-2 (3) MTC and hyperparathyroidism
 ret protooncogene (RET) mutation.

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This gene provides instructions for producing a protein that
is involved in signaling within cells. Mutations in the RET
gene overactivate the protein's signaling function, which
can trigger cell growth and division in the absence of
signals from outside the cell. This unchecked cell division
can lead to the formation of tumors in endocrine glands
and other tissues.
Their first-degree relatives may have specific RET
mutation.
Patients may present with:

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1. Medullary thyroid carcinoma (> 90%);it starts by hyperplasia of the
calcitonin producing cells which is a precursor of MCT multicentric

2. Hyperparathyroidism (2050%), due to hyperplasia or multiple

adenomas in over 70% of cases;

3. Pheochromocytomas (2035%), in the adrenal bed which are

often bilateral

4. Hirschsprung's disease (congenital megacolon)

Laboratory Studies

Screening for medullary thyroid carcinoma is done with the pentagastrin

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stimulation test basal and stimulated plasma calcitonin (CT)

Screening for pheochromocytomas Urinary catecholamines and metanephrines

after the age of 6 years. Patients with MEN-2 tend to have a higher epinephrine :
norepinephrine ratio.

Serum calcium level every two y and PTH levels screen for hyperparathyroidism.

Imaging Studies
If calcitonin levels are elevated at either baseline or with provocative
testing, evaluate the chest and abdomen for metastatic disease.
Perform CT scanning or MRI for imaging of the adrenals.
MEN Type 3

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Familial, autosomal dominant multiglandular syndrome that is caused by a
mutation of the ret protooncogene (RET) on chromosome 10.

1. Mucosal neuromas (> 90%) with bumpy and enlarged lips and tongue
2. Marfan-like habitus (75%),
3. Adrenal pheochromocytomas (60%) rarely malignant and often bilateral
4. Medullary thyroid carcinoma (80%).
5. Intestinal ganglioneuromas
6. Skeletal abnormalities (87%)
7. Delayed puberty (43%).
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Medullary thyroid carcinoma is aggressive and presents early in
life. Therefore, infants having a parent with MEN 3 receive
genetic screening; those carrying the RET mutation undergo a
prophylactic total thyroidectomy by age 6 months.
 Indviduals at risk of MEN 2
and MEN 3 Negativ
e
Screen for RET mutation
Positive

Basal & Plasma & urine Ca & PTH

stimulated Catecholamines
Calcitonin
Normal Abnormal
Thyroidectomty Negative Positive
Serial Calcitonin
measurement Annual Resection
screening
screening
Annual screening Annual MRI

Unilateral
Bilateral
Adrenalrectomy
Adrenalectomy
Biochemical check
MEN 4 (MEN X syndrome)

Autosomal dominant caused by a mutation in the

CdN1B gene encoding p27
Patients develop parathyroid and anterior pituitary
tumors, which may occur in association with tumors of
the reproductive organs, adrenals and kidneys
CASES
CASE 1
Because of sudden unconsciousness and jerking movement of the entire body, a
31-year-old man was brought to a nearby hospital. His father and his brother had a
malignant thymoma and urinary calculosis. His sister showed the signs of
acromegaly caused by a pituitary tumour.
Physical examination showed no abnormalities except that he showed
stereotyped movements
Fasting plasma glucose was 56 mg/dl.
Serum calcium was 5.7 mEq/l (normal range 4.55.5)
Endocrinological data:
GH 9 ng/ml (<1.5) Prolactin 6.9 ng/ml (1.59.7)
FSH 8.5 mIU/ml (1.813.6) LH 1.6 mIU/ml (1.18.8)
Intact PTH 84 pg/ml (1466} free T3 2.8 pg/ml (2.54.3)
cortisol 15.4 g/dl (<20) Insulin 58 U/ml (511) when plasma
glucose was 80 mg/dl
Gastrin 92 pg/ml (<200).
A contrast-enhanced abdominal CT scan revealed
a tumour mass in the body of the pancreas .
Normal MRI of the pituitary and ultrasonography of the parathyroid glands
Based on the clinical and laboratory findings as well as
his family history, a diagnosis of MEN1 presenting with
insulinomas and hyperparathyroidism was made. In
addition, the existence of a growth hormone-secreting
pituitary adenoma was suggested.
CASE 2
An 18-year-old girl presented with long-term diarrhea and enterocutaneous
fistula. Three months before admission, she developed pain and swelling in the
left lower quadrant of the abdomen and erythema of the same area.She
underwent surgery with probable diagnosis of abscess
She also had primary amenorrhea and a history of hypothyroidism.
On examination, she had a marfanoid habitus, a tall stature, and increased joint
laxity. Blood pressure was 90/60mmHg.

24hrs urine metanephrine: 192mcg/24hr (normal: <350)

24hrs urine normetanephrine: 93mcg/24hr (normal: <600),
Serum albumin: 4.4g/dL (3.55),Cholesterol: 145mg/dL, HDL: 51mg/dL,

TG: 175mg/dL,Iron: 71, TIBC: 406,

24hrs urine calcium: 66g/dL
BUN: 7, Cr: 0.7,Anti-TPO: 14.3,LFT: N
Calcitonin: >2000 (with normal limit up to 140),
CEA: 3689 (with normal limit up to 37).
MEN TYPE 3 was suggested due to the thyroid nodule, marfanoid
appearance, mucosal neuromas, and gastrointestinal tract
abnormalities.
CASE 3
A 50-year-old male patient, one episode of renal colic from renal lithiasis, traumatic fracture
of the sternum.
In 2003, he was complaining of abdominal pain and diarrhoea.
Abdominal CT and MRI detected three solid nodular lesions in the pancreas.
The patient also had two adrenal nodules, one in each gland, without accompanying
hormonal hypersecretion.

A blood gastrin level of 135 ng/L (reference range 25-90) .

The patient was referred to us because of diabetes mellitus secondary to pancreatectomy
He was diagnosed with primary HPT based on the detection of hypercalcemia
Intact PTH level of 204 ng/L (reference range 7-53)
Urine calcium excretion of 13.4 mmol/24h (reference range 2.5-7.5) .
During the two-year follow-up period, serum calcium concentration 3.1 mmol/L (reference
range 2.3-2.7).
Pituitary hormones was carried out but no abnormality was found. A pituitary MRI showed
no microadenoma.
A cervical ultrasound revealed 4 thyroid nodules which appeared to correspond to the
parathyroid.
On suspicion of MEN1, a genetic study was carried out and
the mutation W183C in exon 3 of the MEN1 gene was
detected.