MEN Syndromes (both clinical and pathology)

Question 1

What are MEN syndromes?

Answer 1

Group of inherited diseases that result in Proliferative lesions of multiple endocrine organs

Tumors that arise with MEN disorders

• are seen in younger patients
• arise in multiple different endocrine organs
• tumors are multi focal
• preceded by asymptomatic stages of hyperplasia
• tumors are more aggressive and recur in higher proportion in cases than sporadic endocrine tumors

Question 2

MEN-1

Wermer syndrome

Answer 2

Rare inheritable disorder with 2:100,000 prevalence

Involves abnormalities in

• parathyroid
• pancreas
• pituitary glands
• most common manifestation = primary hyperparathyroidism*
• can be hyperplasia or adenomas of the parathyroid gland
• leading cause of morbidity = pancreas tumors*
• usually multiple microadenoma scattered throughout the pancreas scattered throughout the pancreas

Question 3

What is the most commonly secreted product in MEN-1 associated pancreatic endocrine tumors

Answer 3

Pancreatic Polypeptide

MEN-1 pancreatic tumors can show Zollinger-Ellison syndrome (gastrinoma) , hypoglycemia and neurological manifestations (insulinomas)**

Most common site of gastrinomas = duodenal

Question 4

What is the most frequent anterior pituitary tumor in MEN type 1

Answer 4

Prolactinoma from somatotrophs

Question 5

Pathogenesis of MEN type-1

Answer 5

Caused by germ-line mutations in the MEN1 tumor suppressor gene
- this gene encodes for the protien called “menin”

Menin is a component of several different transcription factor complexes which promote or inhibit tumorgenesis
(Includes B-catenin, AP-1, SMAD, MYC, FPXA2)

Question 6

MEN-2 distinct types

Answer 6

MEN2A (simple syndrome)

• shows pheochromocytoma (40-50% and is almost always bilateral)
• medullary carcinoma of the thyroid (virtually 100% chance and are usually multi focal)
• parathyroid hyperplasia (10-20%)
• always shows elevated calcitonin

MEN2B

• similar to MEN2A except NEVER shows hyperparathyroidism
• also shows neuromas, ganglioneuromas and Marfanoid habitus (NOT SEEN in MEN2A)

Familiarly medullary thyroid cancer

• is a fair net of MEN-2A except only really shows medially thyroid cancer
• also develops at older ages and is more of an indolent course

Question 7

MEN type 2A pathogenesis

Answer 7

Germ-line gain of function mutations in the RET oncogene on chromosome 10q11.2 - this leads to excess glial derived neurotrophic factor (GDNF) binding and results in endocrine cells increasing in growth and differentiation

Question 8

MEN type2B pathogenesis

Answer 8

Germline mutation in RET oncogene that results in a point mutation
- results in increased absence of the RET gene even in absence of the ligand

Question 9

What is the inheritance pattern of all MEN syndromes?

Answer 9

Autosomal dominant

Question 10

What are the classic genetic findings for each MEN?

Answer 10

Ret proto oncogene mutations = MEN 2A/2B

MEN1 = MEN1

CDK1B = MEN4

Question 11

Wermers syndrome (MEN1) high yield

Answer 11

Includes the three P’s of affected organs

1) parathyroid
2) pancreatic islets
3) pituitary gland

Most common clinical feature = hyperparathyroidism (90%)

Greatest prevalence = pancreatic islet tumors (16-38%)

Most common MEN (2-20:100,000)

Most commonly is seen in 30-40s

Tumors are usually multiple and high rates of metastasis

Question 12

Clincial features of MEN1

Answer 12

Depends on what neruoendocrine tumors are present

Hypercalcemia
- hyperplasia of parathyroid glands

Zollinger-Ellison syndrome (excessive gastrinomas)

Hypoglycemia
(Excessive insulinomas)
- usually symptoms appear after fasting

Glucose intolerance

Hyperprolactinemia, acromegaly, Cushing

• (anterior pituitary tumors)
• women with hyperprolactinemia = amenorrhea and infertility and galactorrhea
• men = infertility

Diarrhea and hypokalemia and achlorhydria
(Excessive VIPomas)

Carcinoid (excess serotonin)
- thymus, GI or pancreas tumors

Facial angiofibromas, lipomas

Question 13

Biomarkers to test for MEN1

Answer 13

Calcium and PTH (parathyroid)

Gastrin and pH = gastrinoma

Insulinoma = fasting glucose and insulin

Pancreas = imaging (MRI/CT) and VIP/glucagon

Prolactinoma, somatotoma, cortiocortrophoma = Prolactin and IGF-1, GH levels
- also MRI imaging

Adrenal glands = imaging (MRI/CT)

Carcinoid syndrome = (CT/MRI)

Question 14

MEN2 high yield stuff

Answer 14

Shows the following for MEN2A (simple syndrome)

• medullary thyroid carcinoma (near 100%)
• pheochromocytoma
• parathyroid tumors

Contains 2 variants

• 2A and 2B (2A is more common)
• also a smaller variant of just medullary thyroid carcinoma only (this is in older patients (>50) where as MEN1 and MEN2A/B is younger)
• *MEN2B = shows marfanoid features and GI/mucosal neuromas**
• only seen in 5% of MEN2 cases (MEN2A is 95%)

all contain a RET protooncogene mutation

Question 15

What are rare complications of MEN2A

Answer 15

Hirschsprung disease

Cutaneous lichen amyloidosis (rough palpable RA side lesions on the skin)

Question 16

What are the most common MEN2B associated symptoms

Answer 16

Marfonoid habitus

Mucosal neuromas on tongue, eyelids and lipids

Megacolon via hirschsprung disease

Question 17

When should you consider MTC only variant of MEN2?

Answer 17

If history shows > 4 other family members being diagnosed with MTC at > 50 yr old with diagnosis
- also no pheochromocytoma or primary hyperparathyroidism is present!!

Question 18

What is the bio marker to measure for medullary thyroid carcinomas?

Answer 18

Calcitonin levels

- should be high

Question 19

MEN4 high yield

Answer 19

Is essentially MEN1 but has the following other tumors as possibilities

• adrenal
• renal
• thyroid
• gonadal

also shows CDK1B mutations

** pretty much is worked up as MEN1 except when you get to genetic screening you will note no MEN1 mutations and instead DCK1B mutations**