Islet Cell Tumors and MEN Syndromes

Question 1

Describe the epidemiology of pancreatic neuroendocrine tumors (NETs) (aka islet cell tumors)

Answer 1

Rare (3000/yr in US) in comparison to exocrine tumors, mostly in middle-aged patients, mostly sporadic, and mostly (75%) non-functioning

Question 2

T or F. All NETs are considered malignant

Answer 2

T. Except if they are less than 5mm (microadenoma) or insulinomas

Question 3

What is the most common site of METs of NETs?

Answer 3

liver

Question 4

What serum marker is a good diagnostic indication of a pancreatic NET?

Answer 4

chromogranin A (in both functioning and non-functioning), but not very specific

Question 5

What are some common associations in patients with pancreatic NETs?

Answer 5

85% occur in pts. with MEN-1

some in von hippel Lindau syndrome, neurofibromatosis-1, and rarely tuberous sclerosis

Question 6

How does neuroendocrine tumors and islet cell tumors look?

Answer 6

• small, bland, uniform, monotonous, benign-looking cells
• arrnaged in nests (left) or cords (right)
• round to oval nuclei and inconspicious nucleoli
• salt and pepper chromatin
• scant pink eosinophiic grnaular cytoplasm

Question 7

What is this?

Answer 7

salt and pepper chromatin

Question 8

WHO grading for neuroendocrine tumors of the GI, liver, and pancreas are based on what?

Answer 8

mitotic figures and Ki-67 staining

Question 9

Ki-67 is a proliferative (not mitotic) index.

Question 10

What are some types of NETs?

Answer 10

glucagonomas

insulinomas

gastrinomas

somatostatinoma

VIPoma

Question 11

How do glucagonomas present?

Answer 11

RARE and present as anemia, diabetes, and necrolytic migratory erythema (below)

They occur most frequently in perimenopausal and postmenopausal women and are characterized by extremely high plasma glucagon levels.

Question 12

How does insulinomas present?

Answer 12

These are the most common type of pancreatic NET and are generally indolent tumors (87% single benign, 7% multiple benign, and 6% malignant)

Present as epidsodic hypoglycemia (below 50 mg/dL) (confusion, stupor. blurred vision, muscle weakness, sweating, palpitations)

NOTE: 8% are part of MEN-1 syndrome

Histo: abundant amyloid and giant cells

Question 13

How does gastrinomas present?

Answer 13

These are the 2nd most common type of pancreatic NET and typically cause:

Zollinger-Ellison Syndrome (parietal cell hyperplasia, diarrhea in up to 50%, hypersecretion of acid, and recalcitrant peptic ulcers mostly in the small bowel)

Question 14

How does VIPomas present?

Answer 14

Verner-Morrison Syndrome (achlorhydria, severe watery diarrhea, hypokalemia/acidosis/hypovolemia)

Some of these tumors are locally invasive and metastatic.

•Neural crest tumors, such as neuroblastomas, ganglioneuroblastoma,

and ganglioneuromas and pheochro­mocytomas can also be associated with the VIPoma syndrome

Question 15

How does somatostatinomas present?

Answer 15

achlorhydria (absence of hydrochloric acid in the gastric secretions), choleslithiasis (inhibits cholecystokinin relase and hence gallbladder emptying), diabetes (inhibits insulin release), and

steatorrhea (the excretion of abnormal quantities of fat with the feces owing to reduced absorption of fat by the intestine)

NOTE: Only about 10% of pts. have symptoms

Question 16

Answer 16

Question 17

What is this?

Answer 17

Multiple insulinomas in a patient with MEN-1

Question 18

What else can hyperinsulinism be caused by?

Answer 18

focal or diffuse hyperplasia of the islets. This change is found occasionally in adults but is far more commonly encountered as congenital hyperinsulinism with hypoglycemia in neonates and infants.

Question 19

What clinical situations commonly may result in islet hyperplasia?

Answer 19

• maternal diabetes,
• Beckwith-Wiedemann syndrome, and
• rare mutations in the β-cell K + -channel protein or sulfonylurea receptor.

Question 20

How does hyperinsulism in maternal diabetes affect pregnancy?

Answer 20

•In maternal diabetes, the fetal islets respond to hyperglycemia by increasing their size and number. In the postnatal period, these hyperactive islets may be responsible for serious episodes of hypoglycemia. This phenomenon is usually transient.

Question 21

Where else can gastrinomas occur besides the pancreas?

Answer 21

duodenum and peripancreatic soft tissue (aka the gastrinoma triangle)

Question 22

Prognosis of gastrinomas?

Answer 22

Most are malignant and have metastasis at diagnosis

Question 23

Associations of gastrinomas?

Answer 23

25% are in pts with MEN-1 – hyperparathyroidism also present here

NOTE: MEN-1 associated gastrinomas are frequently multifocal while sporadic gastrinomas are single

Question 24

Question 25

What are MEN syndromes?

Answer 25

inherited diseases of multiple endocrine organs that are often multifocal and can be synchronous or metachronous. These typically present in younger pts., show cellular hyperplasia before neoplasm, and are typically more aggressive and recur than similar cases of sporadic endocrine tumors

Question 26

How does MEN1 (Wermer Syndrome) present?

Answer 26

• pituitary involvement, most frequently prolactin-secreting microadenoma
• primary hyperparathyroidism (most common manifestation (80-95%) and commonly the first one seen)- can be hyperplasia or adenoma
• pancreas endocrine tumors (often multiple, aggressive, functional, and the most often what kills patients). Zollinger-Ellison syndrome, associated with gastrinomas, and hypoglycemia, related to insulinomas, are common endocrine manifestations. NOTE: the gastrinomas arising in MEN-1 syndrome are far more likely to be located in the duodenum than in the pancreas

Question 27

Gene for MEN1? MOI?

Answer 27

Gene- MEN1 – tumor suppressor gene – at 11q13 that encodes menin

MOI: AD

Question 28

Mutation of MEN-2?

Answer 28

Gain of function mutation of RET proto-oncogene at 10q11.2

Question 29

MOI of MEN2?

Answer 29

AD. Strong geno-phenotype correlation exists here

Question 30

How does MEN 2A (Sipple Syndrome) present?

Answer 30

• Thyroid – medullary carcinoma in the first two decades of life (almost 100%) with signs of C cell hyperplasia
• Parathyroid – 10-20% get hyperplasia and manifestations of primary hyperparathyroidism
• Adrenal medulla – 50% get pheochromocytomas (only 10% are malignant)

Question 31

How does MEN2B present?

Answer 31

• Thyroid – medullary carcinoma in the first two decades of life
• Adrenal medulla – get pheochromocytomas
• NO HYPERPARATHYROIDISM but do see extraendocrine manifestations such as neuromas/ganglioneuromas at mucosal sites (GI, lips, tongue) and marfanoid habitus

Question 32

Question 33

Question 34

Answer 34

Question 35

Question 36

What is this?

Answer 36

Insulinoma via electron micrograph

Question 37

What is Familial medullary thyroid cancer?

Answer 37

a variant of MEN-2A characterized by medullary thyroid cancers, but not the other characteristic manifestations of MEN-2A. This typically occurs at an older age than MEN-2A and follows a more indolent course

Question 38

NOTE: All persons carrying germline RET mutations are advised to have prophylatic thyroidectomy to prevent the inevitale developement of medullary carcinomas