Describe the epidemiology of pancreatic neuroendocrine tumors (NETs) (aka islet cell tumors)
Rare (3000/yr in US) in comparison to exocrine tumors, mostly in middle-aged patients, mostly sporadic, and mostly (75%) non-functioning
T or F. All NETs are considered malignant
T. Except if they are less than 5mm (microadenoma) or insulinomas
What is the most common site of METs of NETs?
What serum marker is a good diagnostic indication of a pancreatic NET?
chromogranin A (in both functioning and non-functioning), but not very specific
What are some common associations in patients with pancreatic NETs?
85% occur in pts. with MEN-1
some in von hippel Lindau syndrome, neurofibromatosis-1, and rarely tuberous sclerosis
How does neuroendocrine tumors and islet cell tumors look?
-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
What is this?
salt and pepper chromatin
WHO grading for neuroendocrine tumors of the GI, liver, and pancreas are based on what?
mitotic figures and Ki-67 staining
Ki-67 is a proliferative (not mitotic) index.
What are some types of NETs?
How do glucagonomas present?
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.
How does insulinomas present?
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
How does gastrinomas present?
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)
How does VIPomas present?
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
How does somatostatinomas present?
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
What is this?
Multiple insulinomas in a patient with MEN-1
What else can hyperinsulinism be caused by?
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.
What clinical situations commonly may result in islet hyperplasia?
-Beckwith-Wiedemann syndrome, and
-rare mutations in the β-cell K + -channel protein or sulfonylurea receptor.
How does hyperinsulism in maternal diabetes affect pregnancy?
•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.
Where else can gastrinomas occur besides the pancreas?
duodenum and peripancreatic soft tissue (aka the gastrinoma triangle)
Prognosis of gastrinomas?
Most are malignant and have metastasis at diagnosis
Associations of gastrinomas?
25% are in pts with MEN-1 – hyperparathyroidism also present here
NOTE: MEN-1 associated gastrinomas are frequently multifocal while sporadic gastrinomas are single
What are MEN syndromes?
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
How does MEN1 (Wermer Syndrome) present?
-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
Gene for MEN1? MOI?
Gene- MEN1 – tumor suppressor gene – at 11q13 that encodes menin
Mutation of MEN-2?
Gain of function mutation of RET proto-oncogene at 10q11.2
MOI of MEN2?
AD. Strong geno-phenotype correlation exists here
How does MEN 2A (Sipple Syndrome) present?
•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)
How does MEN2B present?
-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
What is this?
Insulinoma via electron micrograph
What is Familial medullary thyroid cancer?
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
NOTE: All persons carrying germline RET mutations are advised to have prophylatic thyroidectomy to prevent the inevitale developement of medullary carcinomas