Multiple Endocrine Neoplasia Syndromes

Question 1

what are MEN syndromes?

Answer 1

a. Group of disorders that affect the endocrine system
b. MEN typically involve tumors (neoplasia) in at least 2 endocrine glands
i. Tumors can be noncancerous (benign) or cancerous (malignant)
c. Clinical features depend on the endocrine glands involved
d. Each syndrome is inherited as an autosomal dominant trait with a high degree of penetrance and variable expressivity
e. Major forms of MEN syndromes are called Type 1, Type 2 (type 2A and type 2B) and type 4

Question 2

prevalence of MEN syndromes

Answer 2

a. MEN1—estimated to vary between 2-20 per 100,000 population
b. MEN2—less common than MEN1
i. Type 2A is the most common form
ii. Type 2B is relatively uncommon, accounting for about 5% of all cases of type 2

Question 3

APUD cells

Answer 3

a. In terms of biological features, MEN tumors arise from the amine precursor uptake and decarboxylation (APUD) group of cellsthese constitute the diffuse system of neuroendocrine cells distributed throughout the body
i. APUD—denotes the capacity of these cells to synthesize and/or secrete biogenic amines formed through activity of the enzyme L-dopa decarboxylase
b. Inherited genetic defects affect different groups of APUD cells and lead to neoplastic development of related cell types in diverse anatomic regions

Question 4

common features of APUD cell population

Answer 4

i. Biogenic amine synthesis
1. Amine precursor uptake
2. Amine (DOPA) decarboxylase
ii. Small polypeptide H synthesis
iii. Membrane bound neurosecretory granule

Question 5

tumors associated with MEN1

Answer 5

i. Parathyroid adenoma—most common—95%
ii. Pancreatic endocrine tumors—50%
iii. Pituitary adenoma—40%
iv. Carcinoid tumors—30%

Question 6

tumors associated with MEN2A

Answer 6

i. Medullary thyroid carcinoma—100%
ii. Bilateral phaechromocytoma—50%
1. Of the adrenal gland—releases catecholamines
iii. Parathyroid adenoma—10%

Question 7

tumors associated with MEN2B

Answer 7

i. Medullary carcinoma of the thyroid—100%
ii. Neuromas—100%
1. Around the mouth area
2. Help us to distinguish type 2A and 2B
iii. Marfanoid habitus—100%
iv. Phaeochromocytoma—50%

Question 8

types of tumors

Answer 8

1. Carcinoid—slow growing type of neuroendocrine tumor
2. Carcinoma—type of cancer related to epithelial cells
3. Adenoma—tends to benign, of epithelial origin but associated with gland
4. Neuroma—tumor within the nerve tissue

Question 9

conditions associated with MEN1

Answer 9

a. pancreas/GI endocrine; pituitary
i. Parathyroid is involved
1. Hyperparathyroidism
2. Hypercalcemia
3. Possible Zollinger Ellison syndrome
4. Various pituitary path
a. Acromegaly
b. Cushing syndrome
c. Galactorrhea

Question 10

conditions associated with MEN2A

Answer 10

a. pheochromocytoma, medullary thyroid cancer (mutation of RET proto-oncogene)
i. Parathyroid is involved
1. Hyperparathyroidism
2. Hypercalcemia
3. Medullary carcinoma—C cells are involved here, and they release calcitonin, so hence…
4. Increased calcitonin
5. Increased catecholamines

Question 11

conditions associated with MEN2B

Answer 11

a. Pheochromocytoma, medullary thyroid cancer (mutation of RET proto-oncogene)
i. Mucosal neuromas result
1. Mucosal nodules
2. Marfanoid body habitus
3. Medullary carcinoma—C cells are involved here, and they release calcitonin, so hence…
4. Increased calcitonin
5. Increased catecholamines

Question 12

mutation in MEN Type 1

Answer 12

a. Caused by mutations in the MEN1 gene—encodes a protein known as menin
i. Menin functionally acts as a tumor suppressor
1. Mutations in menin cause unregulated cell division that leads to tumor formation

Question 13

what is the other name for MEN Type 1

Answer 13

Werner Syndrome

Question 14

tumors associated with MEN Type I

Answer 14

i. Parathyroid
ii. Pancreas—endocrine
iii. Pituitary

Question 15

carcinoid tumor and MEN1

Answer 15

a. Carcinoid tumors have also been reported frequently in MEN1 patients
i. Male patients appear to have a predilection for developing carcinoid tumors within the thymus
ii. Women experience bronchial carcinoids whereas men almost never do

Question 16

3 means of diagnosing of MEN1

Answer 16

i. clinical—2 or more MEN1 associated tumors
ii. familial—patient with one MEN1 associated tumor and a first degree relative with MEN1
iii. genetic—an asymptomatic carrier of MEN1 mutation (no biochemical manifestations

Question 17

parathyroid glands and MEN type 1

Answer 17

i. although the parathyroid glands are the most frequently involved organs (95%) and hyperparathyroidism is usually the first manifestation of the syndrome, its presence may not be detected until clinical disease of the pituitary or pancreas has brought the patient to medical attention
1. hyperparathyroidism associated with MEN1 results from hyperplasia of all 4 glands—although it might be gradual

Question 18

endocrine pancreas and MEN Type 1

Answer 18

i. neoplastic transformation of the pancreatic islet cells is the second most common manifestation of MEN1
1. tumors that develop in the pancreas can be benign or malignant
2. most frequent manifestation of MEN1 pancreatic involvement is gastrinoma
a. approx. 1/3 of patients with gastrinoma are associated with MEN1
b. tend to be multifocal and small—hard to discover and treat
3. insulinomas are the second most common type of functional pancreatic tumor in MEN1
4. other pancreatic tumors include: glucagonomas, somatostatinomas, and vasoactive intestinal polypeptide secreting tumors (VIPomas)

Question 19

first manifestation of MEN1

Answer 19

hyperthyroidism

Question 20

second manifestation of MEN1

Answer 20

neoplastic transformation of the pancreatic islet cells is the second most common manifestation

Question 21

pituitary gland and MEN type 1

Answer 21

i. pituitary tumors occur in 50% to 42% of patients with MEN1
1. most tumors are functionally active and secrete prolactin
a. symptoms of hyperprolactinemia are the third most common manifestation of MEN1
i. women: galactorrhea and amenorrhea
ii. men: impotence

Question 22

third manifestation of MEN1

Answer 22

symptoms of hyperprolactinemia

Question 23

if MEN 1 patients develop tumor secreting ACTH or Growth H, then they may present with

Answer 23

Cushing Syndrome or acromegaly

Question 24

what do patients with MEN1 syndrome have an increased frequency of?

Answer 24

1. Patients with MEN1 syndrome have an increased frequency of both functional and non-functional adrenal cortical hyperplasia or adenomas

Question 25

treatment for MEN1

Answer 25

1. Surgical resection of hyperplastic parathyroid tissue
2. Surgical resection of pituitary adenomas or pharmacological management of pituitary adenomas with bromocriptine for prolactinomas and octreotide for acromegaly
3. Subtotal pancreatectomy—removing as many multifocal tumors as possible in patients with endocrine pancreatic tumors
   a. Surgical cure for the associated pancreatic tumors is not usually possible

Question 26

mutation in MEN type 2

Answer 26

RET oncogene
i. RET gene codes for a receptor tyrosine kinase that phosphorylates and activates enzymes critical to cellular development

Question 27

medullary thyroid carcinoma*

Answer 27

a. Most common sign of MEN2 is malignant transformation of parafollicular cells (or C cells)=medullary thyroid carcinoma (MTC)
i. C cells normally elaborate calcitonin and are scattered throughout the thyroid gland

Question 28

most common sign of MEN2 is…

Answer 28

malignant transformation of parafollicular cells (or C cells)=medullary thyroid carcinoma (MTC)

Question 29

what can people develop when they have MEN2?

Answer 29

pheochromocytoma–adrenal gland tumor

Question 30

overall mortality in MEN2

Answer 30

a. MEN2B is more severe
i. Average age of death for patients with MEN2A is 60 years
ii. Patients with MEN2B has an average age of death of 30 years

Question 31

other name for MEN2A

Answer 31

simple syndrome

Question 32

MEN2A

Answer 32

i. Consists of neoplastic transformation of parathyroids, thyroid parafollicular C cells, and adrenal medulla
ii. Parafollicular cells in patients with MEN2A characteristically progress through a state of C cell hyperplasia to nodular hyperplasia to malignant degeneration over a variable period
1. MTC also expresses peptides and Hs not commonly elaborated by C cells, including somatostatin, TRH, VIP, POMC, carcinoembryonic antigen, and neurotensin

Question 33

pheochromocytoma and MEN2A

Answer 33

i. Pheochromocytomas associated with MEN2A secrete greater amounts of epinephrine that sporadic pheochromocytomas

Question 34

cutaneous lichen amyloidosis*

Answer 34

i. itchy skin condition that may be present in some cases of MEN2A

Question 35

mutation associated with MEN2B

Answer 35

i. MEN2B syndrome is the association of MTC and pheochromocytoma with multiple mucosal neuromas in an affected individual
1. MTC associated with this syndrome is more aggressive that other forms
2. Metastatic lesions have been described in infancy
Hyperparathyroidism is not associated with MEN2B

Question 36

hyperparathyroidism and MEN2A

Answer 36

i. Hyperparathyroidism associated with MEN2A is similar to that found in MEN1, but it is less frequent than in MEN1