Adrenal Disorders 1B.) Pheochromocytoma And Neuroendocrine Tumors

Front 1

What are two large topics covered in this lecture?

Back 1

pheochromocytoma and neuroendocrine tumors (NET)

Front 2

What is a feature of pheochromocytoma (PHEO)?

Back 2

catecholamine- producing tumor
-from chromaffin cells of adrenal medulla or sympathetic ganglia

Front 3

what is nomenclature of pheo?

Back 3

-adrenal pheo (pheo = 80-85%)
-extra-adrenal pheo = paraganglioma (15-20%)

Front 4

What is prevalence of pheo for patients screened for secondary causes of hypertension

Back 4

0.1-0.6%

Front 5

What should you know about pheochromocytoma: what about associated hypertension, risk of paroxysm, % tumors that are malignant and % tumors that are familial?

Back 5

associated hypertension = curable
-risk of lethal paroxysm exists
-10% of tumors are malignant
10-20% of tumors are familial

Front 6

Describe pheo signs and symptoms (the spells):

Back 6

-typically last 15-20 minutes to hours
-elicited by variety of stimuli:
food, exercise, drugs, contrast for CT scans, tumor manipulation, and maneuvers that increase intraabdominal pressure

Front 7

What is the "classic triad" associated with pheo?

Back 7

-headache, palpitations, sweating

Front 8

What are genetic (4) and syndromic forms of pheo?

Back 8

15-20% with germline mutations
-typically present at younger age
-4 hereditary syndromes include the following: MEN 2, VHL, NF1, familial paraganglioma!

Front 9

What do you have to know about MEN 2: Where is the AD mutation?

Back 9

In the RET proto-oncogene
-RET = receptor tyrosine kinase activates intracellular pathways
-expressed in cells derived from neural crest
-normally activated by ligand receptor binding
-leads to ligand-independent activation (activating mutations):

Front 10

Features of type 2a MEN:

Back 10

sipple's syndrome:
1.) hyperparathyroidism
2.) pheochromocytoma
3.) medullary thyroi carcinoma

Front 11

features of type 2B MEN:

Back 11

1.) medullary thyroid carcinoma
2.) pheochromocytoma
3.) mucosal neuromas
4.) marfanoid habitus

Front 12

What % of MEN2 develop pheo?

Back 12

50% of MEN2

Front 13

Describe important features of VHL:

Back 13

-AD disorder of VHL tumor suppressor gene (loss of function mutation)
-gene product (pVHL) is involved in degradation of hypoxia-inducible factors (HIFs)

Front 14

What happen when cells are defective in pVHL?

Back 14

They overproduce HIFs, leading to overproduction of HIF-target genes such as VEGF!

Front 15

What are three major manifestations of VHL?

Back 15

1.) renal-cell cysts and carcinoma
2.) retinal/ CNS hemangioblastomas
3.) pheochromocytoma (10-20% ; frequently bilateral)

Front 16

What is important to know about NF1:

Back 16

-AD disorder
-inherited mutation of NF1 tumor suppressor gene (inactivating mutation)
-NF1 gene product is neurofibromin
-Neurofibromin turns off Ras (G protein widely involved in tumorigenesis)

Front 17

What do most NF1 mutations do?

Back 17

-cause truncated neurofibromin which does NOT effectively inhibit ras (inactivating mutation)

Front 18

What are major manifestations of NF1?

Back 18

-multiple fibromas on skin and mucosa
-cafe au lait skin spots
-axillary and inguinal freckling
-iris hamartomas (Lisch nodules)
-pheochromocytomas < 5% Q

Front 19

What to know about Familal paraganglioma?

Back 19

-ad disorder
-gene mutation in one of the subunits (SDHB, SDHC (rare)), SDHD = of the succinate dehydrogenase enzyme complex (Mitochondrial complex II = tumor suppressor gene)

Front 20

What does disruption of the mitochondrial complex II result in?

Back 20

activation of tumor promoting genes such as VEGF -->

Front 21

What are different manifestations of familial paraganglioma?

Back 21

Adrenal pheochromocytoma, extra-adrenal pheo (paraganglioima); head and neck paraganglioma; other tumors (papillary thyroid ca, renal cell ca_

Front 22

Familial paraganglioma: SDHD: effect:

Back 22

penetrance depends on mutation's parent of origin (maternal imprinting)

Front 23

familial paraganglioma: SDHB:

Back 23

-increased risk for malignant paraganglioma:
-metastatic in 35% at the time of diagnosis
-increased risk for renal cell carcinoma and papillary thyroid cancer!!!!

Front 24

Who do you test for pheo?

Back 24

resistant hypertension, paroxysms suggestive of pheo; familial history of pheo; genetic predispositin (MEN2); past history of resected pheo and present history of recurrent hypertension or spells and adrenal incidentaloma

Front 25

Describe the biochemical testing for pheo?

Back 25

24 hour urine collection for fractionated catecholamines and metanephrins (sensitivity & specificity of 98%)

Front 26

What do you have to know about plasma metanephrines (MN)?

Back 26

-metanephrines are continuously released from pheo
-there is a very high sensitivity (97-100%) but a low specificity (85-89%)
-conveniently performed
-problem is that there are a lot of false positive results: confirm (or refute) positive screening plasma MN with more specific 24 hour urine collection for catechlamines and MN

Front 27

Describe the interference with pheo testing: Many substances can either...

Back 27

a.) raise level of catecholamiens or metabolites
b.) interfere with assay

Front 28

What are two dynamic tests for pheo?

Back 28

1.) clonidine suppression test (clonidine supresses catecholamine release but failure to suppress after clonidine --> pheo)
2.) glucagon stimulation test:
in pheo, glucagon causes NE levels to rise 3x; not recommended b/c test can be fatal!

Front 29

What do pheo's look like on T2-weighted MRI images?

Back 29

-light bulb sign: bright white!

Front 30

What are two other important functional imaging tests?

Back 30

1.) I-123 MIBG --> metaiodobenzylguanidine
--> adjunct to CT/MRI or when CT/MRI fail to find tumor
--> also indicated if the adreanl pheo > 10 cm due to increased risk of malignant disease and paragangliomas
sensitivity of 80 and specificity of 99%

2.) octreotide scan

3.) PET

Front 31

Describe the pheo surgery:

Back 31

laparoscopic surgery
-low operative mortality IF appropriate preoperative management is taken Operative risks = hypertensive crisis, cardiac ischemia, cardiac arrytmias, pulmonary edema

Front 32

Describe pre-op managemetn:

Back 32

start 7-10 days prior to surgery (alpha-blockade) --> phenoxybenzamine: (noncompetitive irreversible inhibition of alpha-adrenergic receptors)
-side effects
-competitive shorter-acting alpha 1 antagonists (prazosin, doxazosin sometimes used)

-beta blockade: propanolol and atenolol (especially if tachyarrythmias)

Front 33

Why doe the alpha blockade always come before the beta blockade?

Back 33

a.) vascular smooth:
alpha adrenergic effect --> vasoconstrition
beta adrenergic effect --> vasodilation

b.) If beta blockers given before alpha blockade, unopposed alpha-adrenergic vasoconstriction occurs and leads to hypertensive crisis!

Front 34

What are different preoperative options?

Back 34

1.) labetolol (combined alpha and beta blocker)
2.) calcium channel blockers
3.) metyrosine (alpha-methyl paratyrosine)
-tyrosine hydroxylase inhibitor, blocks rate-limiting step of catecholamine synthesis
-side effects: somnolence, depression

Front 35

describe preoperative oral salt loading:

Back 35

-encourage high salt diet and liberal fluid intake:
-reduces orthostatic hypotension from phenoxybenzamine
-reduces postoperative hypotension

Front 36

describe postoperative management: 2 risks in particular:

Back 36

1.) risk of hypotension (catecholamien levels fall: alpha blockade from phenoxybenzamine is still active)
-reduced risk with pre-operative volume loading (salt and fluid)

2.) risk of hypoglycemia: catecholamines suppress insulin secretion and insulin level "rebound" after pheo is removed

Front 37

What are Neuroendocrine tumors?

Back 37

rare, slow-growing neoplasms characterized by their ability to store and secrete different peptides and neuroamines in response to stimuli

Front 38

Where to NET arise?

Back 38

-arise throughout the body; in respiratory tract, in pancreas, and anywhere along GI tract inc. appendix ; may be functional or nonfunctional

Front 39

Percentages of pancreatic NET in MEN1, VHL, and NF1?

Back 39

-MEN1: 80-100%
-VHL: 10-17%
-NF1: 10%

Front 40

Describe the three major pancreatic NET's in MEN1 (autosomal dominant disorder that has inactivation mutation of ts gene MEN1 or menin):

Back 40

-gastrinoma, insulinoma, nonfunctional (most common NETs in MEN1)

Front 41

What are 6 clinical syndromes related to neuroendocrine tumors?

Back 41

carcinoid, gastrinoma, insulinoma, glucagonoma, VIpoma, somatostatinoma

Front 42

What causes carcinoid syndrome:

Back 42

tumor secretion of serotonin and vasoactive peptides such as histamine, tachykinins, kallikrein, prostglandins:

Front 43

What symptoms characterize carcinoid syndrome?

Back 43

flushing, diarrhea, wheezing, right sided valvular heart disease

Front 44

What is the action of the liver in preventing carcinoid syndrome and what is testing of this syndrome?

Back 44

liver inactivates serotonin, so carcinoid syndrome implies tumor effluent that reaches systemic circulation without passing through liver and bypasses hepatic inactivation
testing: urinary excretion of 5-HIAA (serotonin metabolite)

Front 45

What is a gastrinoma;

Back 45

functional NEt secreting gastrin
-gastrin is a hjormoen that stimulates gastrin acid secretion

Front 46

What is zollinger-ellison syndrome (ZES) associated with and what are the symptoms?

Back 46

associated with gastrinoma
-abdominal pain: (peptic ulcer disease and GE reflux disease)

-diarrhea:

Front 47

What percent of gastrinomas found in duodenum in patients with sporadic ZES and MEN1?

Back 47

60% in duodenum in patients with sporadic ZES and > 85% with MEN1:

Front 48

Compare number of gastrinomas in sporadic ZES versus MEN1? What is the testing like?

Back 48

-single in sporadic ZEs and multiple in MEN1
-malignant in 60-90% of cases: and pancreatic tumors are more aggressive and more likely to metastasize

-Testing: very high gastrin and low stomach pH (secretin test: normal response: gastrin decreases and response in gastrinoma: gastrin rises)

Front 49

What is an insulinoma?

Back 49

functional NET secretin insulin
-presents with symptoms of hypoglycemia: (will be discussed at length in the lecture on hypoglycemia)

Front 50

What is VIPoma?

Back 50

Functional NET secreting VIP
-WDHA syndrome:
watery diarrhea
hypokalemia
achlorridia

Verner-Morrison syndrome or pancreatic cholera

Front 51

VIPoma: tumor description/types:

Back 51

usually single tumors
-presentation in 70-80% of cases = metastatic
-diagnosis: elevated VIP level in patient with large volume secretory diarrhea

Front 52

What to know about glucagonoma?

Back 52

-functional NET secreting glucagon: (Sweet syndrome)
-4D syndrome: dermatosis, depression, DVT, diarrhea:
-diabetes

Front 53

What are other features of glucagonoma?

Back 53

-single and large tumors
-associated with liver metastases in more than 60%
-diagnosis: elevated glucagon levels (usually 500-1000 pg/mL, normal < 50) in presence of appropriate symptoms

Front 54

somatostatinoma;

Back 54

functional NET secretin somatostatin
-somatostatin: ubiquitous hormoen with inhibitory functions:
syndrome: diabetes, gallbladder disease, diarrhea, steatorrhea;
testing: somatostatin level
-50% of patients have MEn1 and NF1; (other endocrinopathies)