MEN syndrome

Question 1

Define hyperplasia

Answer 1

Increase in the number of cells in tissue or organ in response to a stimulujs

Question 2

How many parathyroid glands are mostly affected by hyperplasia?

Answer 2

The 4 glands

Question 3

What is the microscopic picture of hyperplasia of parathyroid?

Answer 3

-Microscopically, the most common pattern seen is that of chief cell hyperplasia, which may involve the glands in a diffuse or multinodular pattern
-Less commonly, the constituent cells contain abundant water-clear cells (‘water-clear cell hyperplasia)
-In many instances there are islands of oxyphils, and poorly developed, delicate fibrous strands may envelop the nodules

Question 4

The patient developed stupor, confusion and hypoglycaemia, why do you think that happened?

Scenario: man with parathyroidectomy, pancreatic mass

Answer 4

Insulinoma

Question 5

What cells are insulinomas derived from?

Answer 5

Beta cell of islets of langerhans

Question 6

What other causes of unresponsive hypoglycaemia do you know?

Answer 6

-Abnormal insulin sensitivity
-Diffuse liver disease
-Inherited glycogenoses
-Ectopic production of insulin by certain retroperitoneal fibromas and fibrosarcomas

Question 7

What is the clinical picture of insulinoma?

Answer 7

-Confusion
-Stupor
-Loss of consciousness (blood glucose 2.5mmol/L or less)

–> these episodes are precipitated by fasting or excercise
–> promptly relieved by feeding or parentaral administration of glucose

Question 8

Biochemical diagnosis of insulinoma

Answer 8

-High circulating levels of insulin
-High insulin to glucose ratio

Question 9

What do you suspect as another pathology in this patinet?

Scenario: man with parathyroidectomy, pancreatic mass

Answer 9

MEN 1

Question 10

What gene mutations occur in insulinoma?

Answer 10

-MEN 1 (also implicated in a number of sporadic neuroendocrine tumours)
-Loss of function mutations in tumour suppressor genes which result in activation of oncogenic mammalian TOR (mTOR) signalling pathway (PTEN)
-Inactivation in genes involved in telomere maintenance e.g. death-domain associated protein (DAXX)

Question 11

What is the two hit hypothesis?

Answer 11

-Like all genes, tumour suppressor genes may undergo a variety of mutations: however, most loss of function mutations that occur in tumour suppressor genes are recessive in nature. Thus, in order for a particular cell to become cancerous, both of the cell’s tumour suppressor genes must be mutated. This idea is known as the ‘two hit’ hypothesis.

Question 12

What is a telomere?

Answer 12

-A telomere is a region of repetitive nucleotide sequences at each end of a chromosome, which protects the end of the chromosome from deterioration or from fusion with neighbouring chromosomes.

Question 13

What is apoptosis?

Answer 13

Programmed cell death.

Question 14

Scenario: female with thyroid nodule, elevated calcitonin levels

What is the single best test to diagnose?

Answer 14

FNAC

Question 15

Pathology report: FNAC showed malignant cell features, amyloid deposits, immunohistochemistry stains positive with calcitonin, stains negative for thyroxine

What type of cancer is this and why?

Answer 15

-Medullary thyroid cancer
-Amyloid deposits, calcitonin positive on IHC

Question 16

What cells are present in medullary thyroid carcinoma?

Answer 16

-Parafollicualr C cells

Question 17

What is IHC in simple words

Answer 17

-Method of localising specific antigens in tissues or cells based on antigen-antibody recognition

Question 18

How does IHC work?

Answer 18

-Antibodies are linked to an enzyme or fluorescene dye. When the antibodies bind to the antigen in the tissue sample, the enzyme or dye is activated, and the antigen can then be seen under a microscope.

Question 19

What is the type of antigen-antibody reaction in IHC?

Answer 19

-Complement fixation

Question 20

What is TNM thyroid

Answer 20

-Tx: cannot be assessed
-T0: no evidence f primary
-T1: limited to thyroid, 1cm or less
-T2: limited to thyroid >1cm but <4cm
-T3: limited to thyroid >4cm
-T4: extending beyond capsule, any size

Question 21

If patient developed hypertension, what do you think they might have?

Answer 21

Phaeochromocytoma

Question 22

How do you diagnose phaeochromocytoma?

Answer 22

Plasma:
-Gold standard: free metanephrine
-Chromogranin A can be raised but is non specific

Urine
-24 hr urinary metanephrine if plasma metanephrine unavailable

Imaging:

Localisation
–> CT
–> MRI

Functional imaging
–> PET
–> MIBG scintigraphy

Question 23

If phaeochromocytoma was familial (MEN 2a) what other condition would you suspect?

Answer 23

-Hyperparathyroidism secondary to parathyroid hyperplasia

Question 24

Describe MEN 1/causative gene

Answer 24

Three P;s

-Parthyroid (95%): parathyroid adenoma
-Pituitary (70%): prolactinoma/ACTH/Growth hormone secreting adenoma
-Pancreas (50%): islet cell tumours/zollinger ellison syndorme

Most common presentaiton = hypercalcaemia

MENIN gene (chromosome 11)

Autosomal dominant

Question 25

Describe MEN 2

Answer 25

2a
-Hyperparathyroidism (usually hyperplasia)
-Phaeochromocytoma
-Medullary thyroid cancer

RET oncogene (chromosome 10)

Autosomal dominant

2b:
Same as 2a with addition of:
–> marfanoid body habitus
–> mucosal neuromas

RET oncogene (chromosome 10

Autosomal dominant

Question 26

How would you treat medullary thyroid cancer?

Answer 26

-Total thyroidectomy with block neck dissection