Pheochromocytoma
Dr. Atallah Al-Ruhaily
Pheochromocytoma
1.
2.
Catecholamine Physiology/Pathophysiology
Clinical Presentation
1.
2.
3.
Diagnosis
1.
2.
4.
Epidemiology
Signs & Symptoms
Biochemical
Localization
Management
1.
2.
3.
4.
Preoperative
Operative
Postoperative
Pregnancy
Catecholamine Producing Tumors
Neural Crest
Sympathoadrenal Progenitor Cell
(Neuroblasts)
Chromaffin Cell
Neuroblastoma
Sympathetic Ganglion Cell
Intra-adrenal Extra-adrenal
Pheochromocytoma
Ganglioneuroma
Catecholamine Producing Tumors
Pheochromocytoma
Paraganglioma
(extra-adrenal pheo)
Originate in extra-adrenal sympathetic chain/chromaffin tissue
Ganglioneuroma
Behave like paraganglioma biochemically
Catecholamine Producing Tumors
Neuroblastoma
Common malignancy in children, adrenal or sympathetic chain
Catecholamine humoral effects usually minor
Rapid growth & widespread metastasis
Some differentiate and spontaneously regress
Rx complex (surgery, XRT, chemotherapy)
Cheodectoma
Carotid body, behave like paraganglioma biochemically
Glomus
jugulare tumor
Intracranial branch of CN IX and X
Behave like paragangliomoa biochemically
Catecholamines
Tyrosine
TH
L-Dopa
Dopamine
Metabolites
MAO, COMT
DBH
Homovanillic acid
(HVA)
NorepinephrineCOMT Normetanephrine
PNMT
Epinephrine
MAO
COMT
Tumor Secretion:
Large Pheo: more metabolites
(metabolized within tumor before release)
Small Pheo: more catecholamines
Sporadic Pheo: Norepi > Epi
Familial Pheo: Epi > Norepi
Paraganglioma: Norepi
Cheodectoma, glomus jugulare: Norepi
Gangioneuroma: Norepi
Malignant Pheo: Dopamine, HVA
Neuroblastoma: Dopamine, HVA
Metaneprine
MAO
Vanillymandelic Acid
(VMA)
PNMT:
Phenylethanolamine-NMethyl Transferase
COMT : Catechol-O-Methyl
Ttransferase
MAO: Mono-Amine Oxidase
Adrenergic Receptors
Alpha-Adrenergic
Receptors
1: vasoconstriction, intestinal relaxation, uterine
contraction, pupillary dilation
2: presynaptic NE (clonidine), platelet aggregation,
vasoconstriction, insulin secretion
Beta-Adrenergic
Receptors
1: HR/contractility, lipolysis, renin secretion
2: vasodilation, bronchodilation, glycogenolysis
3: lipolysis, brown fat thermogenesis
Pheochromocytoma
1.
2.
Catecholamine Physiology/Pathophysiology
Clinical Presentation
1.
2.
3.
Diagnosis
1.
2.
4.
Epidemiology
Signs & Symptoms
Biochemical
Localization
Management
1.
2.
3.
4.
Preoperative
Operative
Postoperative
Pregnancy
Pheochromocytoma
0.01-0.1%
of HTN population
Found in 0.5% of those screened
=F
3rd to 5th decades of life
Rare, investigate only if clinically suspicion:
Signs or Symptoms
Severe HTN, HTN crisis
Refractory HTN (> 3 drugs)
HTN present @ age < 20 or > 50 ?
Adrenal lesion found on imaging (ex. Incidentaloma)
Pheo: Signs & Symptoms
The
five Ps:
The
Pressure (HTN)
Pain (Headache)
Perspiration
Palpitation
Pallor
90%
80%
71%
64%
42%
Paroxysms
Classical Triad:
Pain (Headache), Perspiration, Palpitations
Lack of all 3 virtually excluded diagnosis of pheo in a series of
> 21,0000 patients
Pheo: Paroxysms, Spells
10-60
min duration
Frequency: daily to monthly
Spontaneous
Precipitated:
Diagnostic procedures, I.A. Contrast (I.V. is OK)
Drugs (opiods, unopposed -blockade, anesthesia induction,
histamine, ACTH, glucagon, metoclopramide)
Strenuous exercise, movement that increases intra-abdo
pressure (lifting, straining)
Micturition (bladder paraganlgioma)
Pheo: Hypotension!
Hypotension
(orthostatic/paroxysmal)
occurs in many patients
Mechanisms:
ECFv contraction
Loss of postural reflexes due to prolonged
catecholamine stimulation
Tumor release of adrenomedullin (vasodilatory
neuropeptide)
Pheo: Signs & Symptoms
N/V, abdo
pain, severe constipation (megacolon)
Chest-pains
Anxiety
Angina/MI with normal coronaries:
Catecholamine induced: myocardial oxygen consumption or
coronary vasospasm
CHF
HTN hypertrophic cardiomyopathy diastolic dysfn.
Catechols induce dilated cardiomyopathy systolic dysfn.
Cardiac
dysrhythmia & conduction defects
Pheo: Signs (metabolic)
Hypercalcemia
Associated MEN2 HPT
PTHrP secretion by pheo
Mild
glucose intolerance
Lipolysis
Weight-loss
Ketosis > VLDL synthesis (TG)
Pheo: Rule of 10
10%
extra-adrenal (closer to 15%)
10% occur in children
10% familial (closer to 20%)
10% bilateral or multiple (more if familial)
10% recur (more if extra-adrenal)
10% malignant
10% discovered incidentally
Familial Pheo
MEN 2a
50% Pheo (usually bilateral), MTC, HPT
MEN 2b
50% Pheo (usually bilatl), MTC, mucosal neuroma, marfanoid
habitus
Von Hippel-Landau
50% Pheo (usually bilat), retinoblastoma, cerebellar
hemangioma, nephroma, renal/pancreas cysts
NF1 (Von Recklinghausen's)
2% Pheo (50% if NF-1 and HTN)
Caf-au-lait spots, neurofibroma, optic glioma
Familial paraganglioma
Familial pheo & islet cell tumor
Other: Tuberous sclerosis, Sturge-Weber, ataxia-telangectgasia,
Carneys Triad (Pheo, Gastric Leiomyoma, Pulm chondroma)
Pheochromocytoma
1.
2.
Catecholamine Physiology/Pathophysiology
Clinical Presentation
1.
2.
3.
Diagnosis
1.
2.
4.
Epidemiology
Signs & Symptoms
Biochemical
Localization
Management
1.
2.
3.
4.
Preoperative
Operative
Postoperative
Pregnancy
24h Urine Collection
24h
urine collection:
Creatinine, catecholamines, metanephrines,
vanillymandelic acid (VMA), +/-dopamine
HPLC with electrochemical detection or mass spect
Positive
results (> 2-3 fold elevation):
24h Ucatechols > 2-fold elevation
ULN for total catechols 591-890 nmol/d
24h Utotal metanephrines > 1.2 ug/d (6.5 umol/d)
24h U
VMA > 3-fold elevation
ULN 35 umol/d for most assays
24h Urine Collection
Test
Characteristics:
24h Ucatechols
Sen 83% Spec 88%
24h Utotal metanephrines
Sen 76% Spec 94%
24h Ucatechols + Utotal metanephrines Sen 90% Spec 98%
24h UVMA
Sensitivity
Sen 63% Spec 94%
increased if 24h urine collection
begun at onset of a paroxysm
24h Urine: False Positive
Drugs:
TCAs, MAO-i, levodopa, methyldopa,
labetalol, propanolol, clonidine (withdrawal), ilicit
drugs (opiods, amphetamines, cocaine), ethanol,
sympathomimetics (cold remedies)
Hold these medications for 2 weeks!
Major physical stress (hypoglycemia, stroke,
raised ICP, etc.)
OSA
Plasma Catecholamines
Drawn
with patient fasting, supine, with an
indwelling catheter in place > 30 min
Plasma total catechols > 11.8 nM (2000 pg/mL)
SEN 85% SPEC 80%
False
positives: same as for 24h urine testing, also
with diuretics, smoking
CRF & ESRD:
Oliguric to Anuric 24h Urines inaccurate
Plasma epinephrine best test for pheo in ESRD
Plasma norepi and metanephrines falsely elevated in ESRD
Plasma Metanephrines
Not
postural dependent: can draw normally
Secreted continuously by pheo
SEN 99% SPEC 89%
False Positive: acetaminophen
Biochemical Tests: Summary
SEN
SPEC
Ucatechols
83%
88%
Utotal metanephrines
76%
94%
Ucatechols+metaneph
90%
98%
UVMA
63%
94%
Plasma catecholamines
85%
80%
Plasma metanephrines
99%
89%
Suppression/Stimulation Testing
Clonidine
suppression
May precipitate hypotensive shock!
Unlike normals, pheo patients wont suppress their
plasma norepi with clonidine
Glucagon
stimulation
May precipitate hypertensive crisis!
Pheo patients, but not normals, will have a > 3x
increase in plasma norepi with glucagon
Localization: Imaging
CT abdomen
Adrenal pheo SEN 93-100%
Extra-adrenal pheo SEN 90%
MRI
> SEN than CT for extra-adrenal pheo
Localization: Imaging
CT abdomen
Adrenal pheo SEN 93-100%
Extra-adrenal pheo SEN 90%
MRI
> SEN than CT for extra-adrenal pheo
MIBG
Scan
SEN 77-90% SPEC 95-100%
MIBG Scan
123I
or 131I labelled metaiodobenzylguanidine
MIBG catecholamine precurosr taken up by the
tumor
Inject MIBG, scan @ 24h, 48h, 72h
Lugols 1 gtt tid x 9d (from 2d prior until 7d after
MIBG injection to protect thyroid)
False negative scan:
Drugs: Labetalol, reserpine, TCAs, phenothiazines
Must hold these medications for 4-6 wk prior to scan
Localization: Nuclear medicine
MIBG
111Indium-pentreotide
Some pheo have somatostatin receptors
PET
F-fluorodeoxyglucose (FDG)
6-[18F]-fluorodopamine
18
Pheochromocytoma
1.
2.
Catecholamine Physiology/Pathophysiology
Clinical Presentation
1.
2.
3.
Diagnosis
1.
2.
4.
Epidemiology
Signs & Symptoms
Biochemical
Localization
Management
1.
2.
3.
4.
Preoperative
Operative
Postoperative
Pregnancy
Pheo Management
Prior
to 1951, reported mortality for excision of
pheochromoyctoma 24 - 50 %
HTN crisis, arrhythmia, MI, stroke
Hypotensive shock
Currently, mortality:
0 - 2.7 %
Preoperative preperation, -blockade?
New anesthetic techniques?
Anesthetic agents
Intraoperative monitoring: arterial line, EKG monitor, CVP
line, Swan-Ganz
Experienced
& Coordinated team:
Endocrinologist, Anesthesiologist and Surgeon
Preop W/up
CBC,
lytes, creatinine, INR/PTT
CXR
EKG
Echo
(r/o dilated CMY 2 catechols)
Preop Preperation Regimens
Combined
+ blockade
Phenoxybenzamine
Selective 1-blocker (ex. Prazosin)
Propanolol
Metyrosine
Calcium
Channel Blocker (CCB)
Nicardipine
Preop: + blockade
Start
at least 10-14d preop
Allow sufficient time for ECFv re-expansion
Phenoxybenzamine
Special pharmacy access only (no DIN)
Drug of choice
Covalently binds -receptors (1 > 2)
Start 10 mg po bid increase q2d by 10-20 mg/d
Increase until BP cntrl and no more paroxysms
Maintenance 40-80 mg/d (some need > 200 mg/d)
Salt load: NaCl 600 mg od-tid as tolerated
Preop: + blockade
Phenoxybenzamine
Side-effect: orthostasis with dosage required to normalized
seated BP, reflex tachycardia
Drawback: periop hypotension/shock unlikely to respond to
pressor agent.
Selective
(contd)
1-blockers
Prazosin, Terazosin, Doxazosin
Some experience with Prazosin for Pheo preop prep
Not routinely used as incomplete -blockade
Less orthostasis & reflex tachycardia then phenoxybenzamine
Used more for long-term Rx (inoperable or malignant pheo)
Preop: + blockade
-blockade
Used to control reflex tachycardia and prophylaxis
against arrhythmia during surgery
Start only after effective -blockade (may ppt HTN)
If suspect CHF/dilated CMY start low dose
Propanolol most studied in pheo prep
Start 10 mg po bid increase to cntrl HR
Preop: + blockade
If
BP still not cntrl despite + blockade
Add Prazosin to Phenoxybenzamine
Add CCB, ACE-I
Avoid diuretics as already ECFv contracted
Metyrosine
Preop: + blockade
Meds
given on AM of surgery
Periop HTN:
IV phentolamine
Short acting non-selective -blocker
Test dose 1 mg, then 2-5 mg IV q1-2h PRN or as continuous
infusion (100 mg in 500cc D5W, titrate to BP)
IV Nitroprusside (NTP)
Periop
arrhythmia: IV esmolol
Periop Hypothension: IV crystalloid +/- colloid
Pheo: Rx of HTN Crisis
IV phentolamine
IV NTP
IV esmolol
IV labetalol
combined + blocker
Preop: Metyrosine
Tyrosine
TH
L-Dopa
Dopamine
DBH
Synthetic inhibitor of Tyrosine
Hydroxylase (TH)
Norepinephrine
Special pharm access, no DIN
PNMT
Start 250 mg qid max 1 gm qid
Severe S/Es: sedation, extrapyramidal, diarrhea,
Epinephrine
nausea/vomit, anxiety, renal/chole stones, galactorrhea
Alone may insufficiently cntrl BP and reported HTN crises
during pheo operation
Restrict use to inoperable/malignant pheo or as adjunct to
+ blockade or other preop prep
Preop: CCB
CCB
Nicardipine: most commonly used agent
Nicardipine (France Study)
Block norepi mediated Ca transport into vascular smooth
muscle
Started po 24h to few weeks preop to cntrl BP and allow ECFv
restoration
After intubation IV Nicardipine gtt (start 2.5 ug/kg/min)
IV Nicardipine adjusted to SBP
Stopped prior to ligation of tumor venous drainage
Tachycardia Rx with concurrent IV esmolol
Advantage: periop hypotension may still respond to pressor agents
as opposed to those patients who are completely -blocked
O.R.
Admit
night before for overnight IV saline
Arterial line, EKG monitor, CVP line
Known CHF: consider Swan-Ganz
Regardless of preop medications:
Have ready: IV phentolamine, IV NTP, IV esmolol
Rx hypotension with crystalloid +/- colloid 1 st
Aim for CVP 12 or Wedge 15
Inotropes may not work!
O.R.
Anesthetic
choice:
Enflurane or isoflurane: dont sensitized
myocardium to catecholamines
Halothane: may sensitize heart arrhythmia
Laprascopic
adrenalectomy if tumor < 8cm
Postop
Most
cases can stop all BP meds postop
Postop hypotension: IV crystalloid
HTN free:
5 years 74% 10 years 45%
24h
urine collection 2 wk postop
Surveillance:
24h urine collections q1y for at least 10y
Lifelong f/up
Pheo: Unresectable, Malignant
-blockade
Selective 1-blockers (Prazosin, Terazosin, Doxazosin) 1 st line
as less side-effects
Phenoxybenzamine: more complete -blockade
-blocker
CCB, ACE-I,
etc.
Nuclear Medicine Rx:
Hi dose 131I-MIBG or 111indium-octreotide depending on
MIBG scan or octreoscan pick-up
Sensitize tumor with Carboplatin + 5-FU
Pheo & Pregnancy
Diagnosis
with 24h urine collections and MRI
No stimulation tests, no MIBG if pregnant
1st & 2nd trimester (< 24 weeks):
3rd
Phenoxybenzamine + blocker prep
Resect tumor ASAP laprascopically
trimester:
Phenoxybenzamine + blocker prep
When fetus large enough: cesarian section followed by tumor
resection
