Adrenal Disorders Ii- Pheochromocytoma/neuroendocrine Tumors

Front 1

What are Pheochromocytomas?

Back 1

*"Pheo"

*Catecholamine-producing tumors

*Arise from chromaffin cells of adrenal medulla or sympathetic ganglia

*Nomenclature can be confusing
-Adrenal pheo = "pheo" (80-85%)
-Extra-adrenal pheo = "paraganglioma" (15-20%)

*Prevalence of 0.1 - 0.6% among patients screened for secondary causes of hypertension

Front 2

What do you want to do if you think a pt has a pheo?

Back 2

*Suspect, confirm, localize and resect
-Associated hypertension is curable
-Risk of lethal paroxysm exists
-10% of tumors are malignant
-10-20% are familial

Front 3

Pheo signs and symptoms:

Back 3

*Classically occur in “spells” (paroxysms)
-Typically last minutes (15-20 minutes) to hours

-Can be elicited by variety of stimuli
Food
Exercise
Drugs (e.g. anesthetic agents, etc...most common stimuli)
Contrast for CT scans
Tumor manipulation
Manuevers that increase intraabdominal pressure (even pregnancy)

Front 4

Prevalence of symptoms associated with Pheo:

Back 4

*“Classic Triad” is HA, palpitations, sweating
*BP effects vary (about half get HTN)
*Catecholamines suppress insulin --> hyperglycemia
*Presentation varies...don't have to have whole triad

Front 5

Differential diagnosis of Pheo:

Back 5

"The great mimic"

Front 6

Genetic and Syndromic forms of Pheo:

Back 6

*15-20% with germline mutations
*Typically present at a younger age
*Hereditary syndromes
-Multiple endocrine neoplasia (MEN) type 2
-Von Hippel-Lindau (VHL) syndrome
-Neurofibomatosis type 1 (NF1)
-Familial paraganglioma

Front 7

Multiple endocrine neoplasia (MEN) type 2:

Back 7

*Autosomal dominant mutation of RET proto-oncogene
-RET is a receptor tyrosine kinase that activates intracellular pathways
-RET is expressed in cells derived from neural crest
-RET normally activated by ligand-receptor binding
-Mutation leads to ligand-independent activation (activating mutations)

Front 8

Describe Multiple endocrine neoplasia (MEN) type 2 subtypes:

Back 8

*Type 2A (Sipple’s syndrome):
-Medullary thyroid CA
-Pheochromocytoma
-Hyperparathyroidism


*Type 2B:
-Medullary thyroid CA
-Pheochromocytoma
-Mucosal neuromas
-Marfanoid habitus

50% of MEN2 patients develop pheo

Front 9

Back 9

-Classic pic of pt with MEN2B
-Marfanlike facies

Front 10

Von Hippel-Lindau (VHL) syndrome:

Back 10

Autosomal-dominant disorder of VHL tumor-suppressor gene (loss of function mutation)

Gene product (pVHL) is involved in degradation of hypoxia-inducible factors (HIFs)

Cells defective in pVHL overproduce HIFs, leading to overproduction of HIF-target genes such as vascular endothelial growth factor (VEGF)

*Major manifestations
Renal-cell cysts and carcinoma
Retinal and CNS hemangioblastomas
Pheochromocytoma (10-20%; frequently bilateral)

Front 11

Back 11

Von Hippel-Lindau (VHL) syndrome

Front 12

Neurofibomatosis type 1 (NF1):

Back 12

*Autosomal dominant disorder

*Inherited mutation of NF1 tumor-suppressor gene (inactivating mutation)
-NF1 gene product is neurofibromin
-Neurofibromin turns off ras (a G-protein widely involved in tumorigenesis)

*Most NF1 mutations cause truncated neurofibromin which does not effectively inhibit ras (inactivating mutation)

*Major manifestations
-Multiple fibromas on skin and mucosa
-“Café au lait” skin spots
-Axillary and inguinal freckling
-Iris hamartomas (Lisch nodules)
-Pheochromocytoma (<5%)

Front 13

Back 13

Neurofibomatosis type 1 (NF1)

Front 14

Back 14

Lisch Nodules in NF-1

Front 15

Back 15

Café au lait spots in NF-1

Front 16

Familial paraganglioma:

Back 16

*Autosomal dominant disorder
*Gene mutation in one of the subunits—SDHB, SDHC (rare), SDHD—of the succinate dehydrogenase enzyme complex (mitochondrial complex II = tumor suppressor gene)
*Disruption of mitochondrial complex II activates tumor-promoting genes such as VEGF

*Manifestations
-Adrenal pheochromocytoma
-Extra-adrenal pheo (paraganglioma)
-Head and neck paraganglioma
-Other tumors (e.g. papillary thyroid CA, renal cell CA)
*Presentation depends on which subunit is involved

Front 17

Describe the significance of mutations in the different subunits of the SDH gene:

Back 17

*SDHD
- penetrance depends on the mutation’s parent of origin
- maternal imprinting is protective; paternal is bad

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

Front 18

Summary of AD syndromes associated with Pheo and Paraganglioma:

Back 18

Front 19

Testing for Pheo:

Back 19

*Who:
Resistant hypertension
Paroxysms suggestive of pheo
Family history of pheo
Genetic predisposition (e.g. MEN2)
Past history of resected pheo and present history of recurrent hypertension or spells
Adrenal incidentaloma

Front 20

Metabolism of catecholamines:
by catechol-O-methyltransferase (COMT),
monoamine oxidase (MAO),
aldehyde dehydrogenase (AD), and
phenol-sulfotransferase (PST)

Back 20

Front 21

Biochemical testing for Pheo:

Back 21

*24 hour urine collection for fractionated catecholamines, metanephrines
-Sensitivity 98% and specificity 98%

*Plasma metanephrines (MN)
-Metanephrines are continuously released from pheo
-Very high sensitivity (97-100%) but low specificity (85-89%)
-Conveniently performed
-Problem: Lot of false-positive results; confirm (or refute) positive screening plasma MN with the more specific 24 hour urine collection for catecholamines and MN

Front 22

Interference with pheo testing:

Back 22

Many substances can either:
Raise level of catecholamines or metabolites
Otherwise interfere with assay

Not in table:
-Acetominophen
-Antipsychotics bigtime! Be off them for 2 weeks before testing
-Ethanol

Front 23

Dynamic testing for pheo:

Back 23

*Clonidine suppression test
Clonidine suppresses catecholamine release
Failure to suppress after clonidine --> Pheo

*Glucagon stimulation test
In pheo, glucagon causes NE levels to rise 3X
Not recommended: Test can be fatal!

Front 24

Finding the pheo:

Back 24

*Do not perform imaging studies unless there is “compelling” biochemistry

*CT Abdomen/Pelvis
-Reliable
-Not OK for kids, pregnant women, of if contrast allergy
-Less expensive

*MRI Abdomen/Pelvis
-Reliable
-OK for kids, pregnant women, of if contrast allergy
-More expensive
-Pheo looks really cool on MRI

Sensitivity >95%, specificity >65%

Front 25

Back 25

The “light bulb” sign – Pheo’s are bright white on T2-weighted MRI images

Front 26

Functional imaging for pheos:

Back 26

*Iodine123-MIBG (metaiodobenzylguanidine)
-Adjunct to CT/MRI or when CT/MRI fail to find tumor
-Also indicated if adrenal pheochromocytoma >10 cm due to increased risk of malignant disease and paragangliomas
-Sensitivity 80%, specificity 99%

*Other tests sometimes used
-Octreotide scan
-PET (positron emission tomography)

Front 27

Back 27

Functional imaging for pheo

Front 28

Pheo surgery:

Back 28

*Treatment of choice – laparoscopic surgery

*Low operative mortality IF IF IF appropriate preoperative management

*Operative risks
Hypertensive crisis
Cardiac ischemia
Cardiac arrythmias
Pulmonary edema

Front 29

Preoperative management before pheo surgery:

Back 29

*Start mgmt 7-10 days prior to surgery

*“Alpha-blockade” with Phenoxybenzamine:
-Noncompetitive irreversible inhibition of alpha-adrenergic receptors
-Side effects: orthostatic hypotension, dizziness, syncope, nasal congestion
-Competitive shorter-acting alpha-1 antagonists (prazosin, doxazosin) sometimes used (less hypotension)

*“Beta-blockade”
-Propranolol or atenolol
-Especially if tachyarrythmias

Front 30

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

Back 30

*Vascular smooth muscle
Alpha-adrenergic effect --> Vasoconstriction
Beta-adrenergic effect --> Vasodilation

*If beta-blockers are given before alpha-blockade, unopposed alpha-adrenergic vasoconstriction can occur leading to hypertensive crisis

Front 31

What are some other pre-operative management before pheo surgery besides alpha/beta blocking?

Back 31

*Labetolol--a combined alpha- and beta-blocker

*Calcium-channel blockers

*Metyrosine (Alpha-methyl-paratyrosine)
A tyrosine hydroxylase inhibitor
Blocks rate-limiting step of catecholamine synthesis
Side effects: somnolence, depression

Front 32

What diet considerations do we need to have for patients prior to pheo surgery?

Back 32

*Preoperative oral salt loading
*Encourage high-salt diet and liberal fluid intake
-Reduces orthostatic hypotension from phenoxybenzamine
-Reduces postoperative hypotension

Front 33

Postoperative management in pheo surgery:

Back 33

*Risk of hypotension
-Catecholamine levels fall
-Alpha-blockade from phenoxybenzamine still active
-Reduced risk with pre-operative volume loading (salt and fluid)

*Risk of hypoglycemia
-Catecholamines suppress insulin secretion
-Insulin levels “rebound” after pheo removed

Front 34

Neuroendocrine Tumors (NET):

Back 34

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

*Arise throughout the body
-Respiratory tract
-Pancreas
-Anywhere along GI tract inc. Appendix

*May be functional or nonfunctional
*May arise sporadically or as part of hereditary syndrome
*Pancreatic NETs – MEN 1 (80-100%)
VHL (10-17%)
NF1 (10%)

Front 35

Multiple Endocrine Neoplasia Type 1 (MEN1):

Back 35

*Autosomal dominant disorder
*Inactivating mutation of the tumor suppression gene MEN1 (menin)

*Major manifestations (the 3 Ps)
-Hyperparathyroidism
-Pituitary adenomas
-Pancreatic NET

Front 36

Most common NETs in MEN1?

Back 36

Pancreatic NETs: Gastrinoma, Insulinoma, Nonfunctional

Front 37

Types of neuroendocrine tumors:

Back 37

Carcinoid syndrome
Gastrinoma
Insulinoma
Glucagonoma
VIPoma
Somatostatinoma

Front 38

Big table summary of NETs:

Back 38

Front 39

Carcinoid syndrome:

Back 39

*Due to tumor secretion of serotonin and other vasoactive peptides (histamine, tachykinins, kallikrein, prostaglandins)

*Classified as foregut, midgut, and hindgut carcinoids.

*Carcinoid syndrome:
Flushing
Diarrhea
Wheezing
Right-sided valvular heart disease

*The liver inactivates serotonin, so the carcinoid syndrome usually implies tumor effluent that reaches systemic circulation without passing through liver and bypasses hepatic invactivation

*Testing: Urinary excretion of 5-HIAA (serotonin metabolite)

Front 40

What are some factors that confound results of 5-HIAA testing?

Back 40

Coffee can be a big one. Stop 3 days before testing.

Front 41

Gastrinoma:

Back 41

*Functional NET secreting gastrin
*Gastrin – hormone that stimulates gastric acid secretion

*Zollinger-Ellison syndrome (ZES)
- Abdominal pain
-Peptic ulcer disease
-Gastroesophageal reflux disease
- Diarrhea

Front 42

What's the different b/t gastrinomas in MEN1 pts and ZES pts?

How aggressive are the tumors?
How do we test for them?

Back 42

*60% are found in the duodenum in patients with sporadic ZES and >85% with MEN 1
*Single in sporadic ZES and multiple in MEN 1
*Malignant in 60-90% of cases
*Pancreatic tumors are more aggressive and likely to metastasize, esp to liver

*Testing
-Very high gastrin level and low stomach pH are indicative
-Secretin test
-Normal response: Gastrin decreases
-Response in gastrinoma: Gastrin rises

*If pt is on a ppi, that can increase the gastrin level; must stop ppi 1-2 weeks before the test for gastrin.

Front 43

Insulinoma:

Back 43

-Functional NET secreting insulin
-Presents with symptoms of hypoglycemia

Front 44

Describe VIPomas:

Back 44

*Functional NET secreting VIP (Vasoactive intestinal peptide)

*“WDHA syndrome”
Watery diarrhea
Hypokalemia
Achlorhydria

*Also called “Verner-Morrison syndrome” or pancreatic cholera

Front 45

Biologic Action and Clinical Signs of VIP:

Back 45

Front 46

Behavior/presentation/diagnosis of VIPomas?

Back 46

*Usually single tumors
*Metastatic at presentation in 70%-80% of cases
*Diagnosis: Elevated VIP level in a patient with large volume secretory diarrhea

Front 47

Glucagonoma:

Back 47

*Functional NET secreting glucagon
*“Sweet” syndrome
*Diabetes
*4D syndrome
-Dermatosis: Necrolytic migratory erythema *hallmark
-Depression
-Deep venous thrombosis
-Diarrhea

Front 48

Back 48

Dermatosis (Necrolytic migratory erythema) in glucagonoma

Front 49

Behavior of glucagonomas:

Back 49

*Generally single and large tumors
*Associated with liver metastases in more than 60%
*Diagnosis: Elevated glucagon levels (usually 500-1000 pg/mL, normal <50) in the presence of appropriate symptoms

Front 50

Somatostatinoma:

Back 50

*Functional NET secreting somatostatin

*Syndrome
-Diabetes
-Gallbladder disease
-Diarrhea/Steatorrhea

*Testing: Somatostatin level
*50% of patients have other endocrinopathies (e.g. MEN 1, NF1)