Transcript Pheochromocytoma (Powerpoint, 576KB)

Pheochromocytoma
William Harper, MD, FRCPC
Endocrinology & Metabolism
Assistant Professor of Medicine
McMaster University
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)


Ganglioneuroma


Originate in extra-adrenal sympathetic chain/chromaffin tissue
Behave like paraganglioma biochemically
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)
Catecholamine Producing Tumors

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
Metabolites
Dopamine
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)
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

M=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 P’s:





Pressure (HTN)
Pain (Headache)
Perspiration
Palpitation
Pallor
90%
80%
71%
64%
42%
• Paroxysms (the sixth P!)

The 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




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
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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)
 Café-au-lait spots, neurofibroma, optic glioma
Familial paraganglioma
Familial pheo & islet cell tumor
Other: Tuberous sclerosis, Sturge-Weber, ataxia-telangectgasia,
Carney’s 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 UVMA > 3-fold elevation
• ULN 35 umol/d for most assays
24h Urine Collection

Test Characteristics:





24h Ucatechols
Sen 83%
24h Utotal metanephrines
Sen 76%
24h Ucatechols + Utotal metanephrines Sen 90%
24h UVMA
Sen 63%
Spec 88%
Spec 94%
Spec 98%
Spec 94%
Sensitivity 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
 Assay not readily available in Canada
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 won’t 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



MRI


Adrenal pheo SEN 93-100%
Extra-adrenal pheo SEN 90%
> 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
Lugol’s 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

18F-fluorodeoxyglucose

6-[18F]-fluorodopamine
(FDG)
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 2º catechols)
Preop Preperation Regimens

Combined  +  blockade



Phenoxybenzamine
Selective 1-blocker (ex. Prazosin)
Propanolol

Metyrosine
 Calcium Channel Blocker (CCB)


Nicardipine
No Randomized Clinical Trials to compare various
regimens!
Preop:  +  blockade

Start at least 10-14d preop


Allow sufficient time for ECFv re-expansion
Phenoxybenzamine

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




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 (cont’d)



Side-effect: orthostasis with dosage required to normalized
seated BP, reflex tachycardia
Drawback: periop hypotension/shock unlikely to respond to
pressor agent.
Selective 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
Synthetic inhibitor of Tyrosine
DBH
Hydroxylase (TH)
Norepinephrine
 Special pharm access, no DIN
PNMT
 Start 250 mg qid  max 1 gm qid
Epinephrine
 Severe S/E’s: sedation, extrapyramidal, diarrhea,
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

Cleveland Clinic Experience





CCB


Only 6 cardiovascular complications
All occurred in patients with preop -blockade
30% received no medications preop if no HTN
Patients not receiving phenoxybenzamine required less fluids
(956 cc intraop, 479 cc POD#1)
Block norepi mediated Ca transport into vascular smooth
muscle
Nicardipine: most commonly used agent
Preop: CCB

Nicardipine (France Study)






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
Preop: CCB

Cleveland Clinic:






Only 10% received phenoxybenzamine
CCB 1st line agents as preop po med
Selective 1-blockers (Prazosin, Terazosin,
Doxazosin) added to CCB if BP still high
Periop arrythmia: IV esmolol
Periop HTN: IV NTP
Periop hypotension:
• IV crystalloid or colloid
• Dopamine, norepi, epi, phenylephrine
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 1st
Aim for CVP 12 or Wedge 15
Inotropes may not work!
O.R.

Anesthetic choice:



Enflurane or isoflurane: don’t 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) 1st 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):



Phenoxybenzamine + blocker prep
Resect tumor ASAP laprascopically
3rd trimester:


Phenoxybenzamine + blocker prep
When fetus large enough: cesarian section followed by tumor
resection