Pheochromocytoma

DR. SUVYL RODRICKS

DR. MEERA KHARBANDA


www.anaesthesia.co.in anaesthesia.co.in@gmail.com
Pheochromocytoma
1. Catecholamine Physiology/Pathophysiology
2. Clinical Presentation
1. Epidemiology
2. Signs & Symptoms
3. Diagnosis
1. Biochemical
2. Localization
4. Management
1. Preoperative
2. Operative
3. Postoperative
4. Pregnancy
Catecholamine Producing Tumors
Neural Crest
Sympathoadrenal Progenitor Cell
(Neuroblasts)
Chromaffin Cell
Sympathetic Ganglion Cell
Intra-adrenal Extra-adrenal
Pheochromocytoma
Ganglioneuroma
Neuroblastoma
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.
Rapid growth & widespread metastasis
Some differentiate and spontaneously regress
Rx complex (surgery, RT, chemotherapy)
Cheodectoma
Carotid body, behave like paraganglioma
biochemically
Glomus jugulare tumor
Intracranial branch of CN IX and X
Behave like paragangliomoa biochemically
Catecholamine Producing Tumors
HISTORY
First recognised by Von Frankel
Pheochromocytoma= dusky colored tumor
Name coined by Pick in 1912
Successful surgery for excision of tumor-
Roux & Mayo ( 1926-27)

Pheochromocytoma
Neuroendocrine tumour of the medulla of the
adrenal glands
Originates from the chromaffin cells along the
paravertebral sympathetic chain extending from
pelvis to base of skull
>95% are abdominal
>90% in adrenal medulla
Secretes excessive amounts of adrenaline and
noradrenaline
80% occur unilateral


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
Tyrosine L-Dopa Dopamine
Norepinephrine
Epinephrine
Catecholamines
Normetanephrine
Metaneprine
PNMT
DBH
COMT
COMT
Metabolites
Homovanillic acid
(HVA)
MAO, COMT
Vanillymandelic Acid
(VMA)
MAO
MAO
TH
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

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. Clinical Presentation
1. Epidemiology
2. Signs & Symptoms
Pheochromocytoma
0.01-0.1% of HTN population
Found in 10% of those screened
M = F
3
rd
to 10
th
decades of life
Rare, investigate only if clinically suspicion:
Signs or Symptoms
Severe HTN, HTN crisis
Refractory HTN (> 4drugs)
HTN present @ age < 20 or > 50 ?
Adrenal lesion found on imaging (ex. Incidentaloma)
Pheo: Signs & Symptoms
The five Ps:
Pressure (HTN) 9%
Pain (Headache) 80%
Perspiration 71%
Palpitation 64%
Pallor 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
Hypertension commonest presenting
complaint
Paroxysmal
episodic
Pheo: Paroxysms, Spells
10- 17%
10-60 min duration
Frequency: daily to monthly
Spontaneous
Precipitated:any activity that displaces abdominal contents
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: Paroxysms, Spells
Sym depend upon the relative proportion of epi & norepi
Excessive secretion of epi & dopamine
D.t epinephrine:
Headache, profuse sweating, palpitations, apprehension
often with a sense of impending doom
Pallor/flushing d. t peripheral adrenergic response
D .t dopamine:
Nausea & vomiting d .t. vasodilation in the GIT



Pheo: Hypotension!
Hypotension (orthostatic/paroxysmal)
occurs in many patients
Mechanisms:
ECF contraction
Loss of postural reflexes due to prolonged
catecholamine stimulation
Tumor release of adrenomedullin (vasodilatory
neuropeptide)
Cardiac manifestations
Sinus tachy, bradycardia , SVT, ventricular ectopics,
V tach
Catecholemine induced inc myocardial oxygen
consumption, coronary vasospasm
Angina/MI
Cardiomyopathy- hypertrophic Cardiomyopathy-
diastolic dysfn- norepi induced
Dilated cardiomyopathy- systolic dysfn- epi induced
CCF with myocarditis
concentric hypertrophy/ assymetrical hypertrophy
Rarely sinus node dysfunction


Neurologic manifestations
Hypertensive encephalopathy ( altered mental status, focal
neurological s/s, seizures )
Stroke d. t. cerebral infarction/ embolus
Intracerebral bleed

Pheo: Signs (metabolic)
Hypercalcemia
Associated MEN2 HPT
PTHrP secretion by pheo
Mild glucose intolerance- supression of insulin secretion,
glycogenolysis ( norepinephrine)
Epi causes stimulation of insulin release thro B2
adrenoceptars- this is offset by the effects of circ norepi
polyuria
Lipolysis- inc epinephrine secr
Weight-loss
Ketosis > VLDL synthesis (TG)




Pheo: malignant
Increased dopamine secretion
Causes inc outlet resistance of the prostatic urethra- pheo
of the bladder
Accomp by hypertension , palpitation sweating , fainting

Familial Pheo
MEN 2a
50% Pheo (usually bilateral)+ medullary Ca Thyroid
+ hyperparathyroidism
MEN 2b
50% Pheo (usually bilatl) mucosal neuroma,
marfanoid habitus
Von Hippel-Landau
50% Pheo (usually bilat), retinoblastoma, cerebellar
hemangioma, nephroma, renal/pancreas cysts
Familial Pheo
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
Diagnosis
1. Biochemical
2. Localization
24h Urine Collection
Positive results (> 2-3 fold elevation):
24h U
catechols
> 2-fold elevation
ULN for total catechols 591-890 nmol/d
24h U
total metanephrines
> 1.2 ug/d (6.5 umol/d)
24h U
VMA
> 3-fold elevation
ULN 35 umol/d for most assays
Detected by high performance liquid chromatography
24h Urine Collection
Test Characteristics:
24h urinary catechol

Sen 83% Spec 88%
24h U total metanephrines

Sen 76% Spec 94%
24h U
catechols
+ U
total metanephrines
Sen 90% Spec 98%
24h U
VMA
Sen 63% Spec 94%
Sensitivity increased if 24h urine collection begun at onset
of a paroxysm
Serum creatinine measured for all collections of urine to
determine adequacy of collection
Plasma free metanephrines sen 99%
spec 89%
Plasma catecholamines sen 84%
spec 81%

Biochemical Tests: Summary
SEN SPEC
U
catechols
83% 88%
U
total metanephrines
76% 94%
U
catechols+metaneph
90% 98%
U
VMA
63% 94%
Plasma catecholamines
85% 80%
Plasma metanephrines
99% 89%
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.)

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
Plasma Catecholamines
CRF & ESRD:
Oliguric to Anuric 24h Urines inaccurate
Plasma epinephrine best test for pheo in ESRD
Plasma norepi and metanephrines falsely elevated in
ESRD
Recurrent pheochromocytoma
Besides others, Chromogranin A levels are done
An acidic , monomeric protein , stored and secreted
with catecholamines
Sen 84% spec 96%
Plasma Metanephrines
Not postural dependent: can draw normally
Secreted continuously by pheo
SEN 99% SPEC 89%
False Positive: acetaminophen

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
90% adrenal,
Extra- adrenal sites- organ of Zuckerlandl( origin of IMA),
bladder, myocardium, mediastenum, carotid & glomus
jugulare bodies
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

123
I or
131
I labelled metaiodobenzylguanidine
Saved for cases where pheo diagnosed biochemically but
no tumor on CT/ MRI
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

111
Indium-pentreotide
Some pheo have somatostatin receptors
PET

18
F-fluorodeoxyglucose (FDG)
6-[
18
F]-fluorodopamine
Pheochromocytoma
1. Management
1. Preoperative
2. Operative
3. Postoperative
4. 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 preparation, -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, electrolytes, creatinine, INR/PTT
CXR
EKG
Echo (r/o dilated CMY 2 catechols)
Preop Preparation 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 ECF re-expansion
Phenoxybenzamine (Dibenzyline)
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
Phenoxybenzamine (contd)
Side-effect: orthostasis with dosage required to
normalized seated BP, reflex tachycardia
Drawback: periop hypotension/shock unlikely to
respond to pressor agents.
Causes presynaptic inhibition of adrenergic control
thus leading to inc in beta adrenergic outflow
Thus beta blockers needed to be given alongside

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
Initial dose 80-120 mg/d
IV 1-10 mg
Beta adrenergic blockers
Propronolol ( contd)
Side effects- may induce cardiac failure, bronchospasm
Oral bioavailability 25% (extensive 1
st
pass
metabolism)
Atenolol- selective B
1
Dose 50- 100 mg/d PO
Max 300 mg/d
IV 2.5 to 10 mg/d
Beta adrenergic blockers
Esmolol selective B
1
for rapid intraop BP
control

Bolus IV 500 /kg/min
Infusion 50 to200 /kg/min
Labetolol mixed +
Dose- 50- 100 mg/d PO
IV 0.25 mg/kg
Not used as asole drug d.t unpredictable control of BP

Preop: + blockade
If BP still not cntrl despite + blockade
Add Prazosin to Phenoxybenzamine
Prazosin (Minipress) competitive, selective
1
blockade
T1/2- 2-3 Hrs
Dose -1-5 mg PO BD
Side effects- postural hypotension reflex tachycardia
No blockade required
Not routinely used as incomplete -blockade
Used more for long-term Rx (inoperable or malignant
pheo)
Other selective
1
blockers- terazosin, doxazocin


Other antihypertensives
CCB-
Diltiazem 60- 120mg/d, max 360mg/d
T1/2- 3to 5 hrs
Side effects- bradycardia, exacerbates cardiac
failure
Nifedepine 30mg/d PO Max. 360mg/d
T1/2-1 to 2 hrs
Side effects- hypotension, peripheral edema
ACE-I- Ramipril
Avoid diuretics as already ECF contracted


Preop: CCB
Nicardipine
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 1
st
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
Preop: + blockade
Meds given on AM of surgery
Periop HTN:
IV phentolamine (Regitine)
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 Hypotension: IV crystalloid +/- colloid
Pheo: Rx of HTN Crisis
IV phentolamine
IV NTP
IV esmolol
IV labetalol combined + blocker
Preop: Metyrosine (Demser)
Synthetic inhibitor of Tyrosine
Hydroxylase (TH)
Start 250 mg qid max 1 gm qid
Severe S/Es: 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
Tyrosine L-Dopa Dopamine
Norepinephrine
Epinephrine
PNMT
DBH
TH
Evaluation of adrenergic
blockade
Roizens criteria
Arterial BP < 160/95 mm Hg in the last 48 hrs prior to
surgery. Recommended to measure in stressful
environment
Mild orthostatic hypotension indicates optimal
adrenergic blockade but not < 80/45.
ECG- free of ST changes for > 2 wks,
Ventricular ectopic < 1 over 5 min


O.R.
Admit night before for overnight IV saline
Arterial line, EKG monitor, CVP line
Known CHF, CAD, low EF(<30): consider Swan-Ganz
Spo2, ETCO2, temperature monitoring
preop medications:
Anxiolytic sedative- benzodiazepine helps dec
catecholamines release
Opoids- morphine preferably avoided as causes
histamine release
Fentanyl, sufentanyl safe
Premedication
Atropine to be omitted- causes tachycardia
Droperidol- antiemetic, blocks adrenoceptor and inhibit
catecholamine uptake & promotes catecholamine release
Anaesthetic technique
General anaesthesia
Regional anaesthesia- mid to low thoracic
Combined regional and general anaesthesia
Preferred- combined regional and general anaesthesia
technique
Here although regional anaesthesia protects against
stresses of surgery, it cannot prevent catecholamine
surges due to tumor manipulation.
In extensive sympathetic blockade, severe hypotension
after tumor removal,


INDUCTION
Essentially imp to give induction agents slowly alomg with
close monitoring of HR and arterial pressure
Thiopentone / propofol widely used
Etomidate causes pain/ involuntary movt
Ketamine not recommended
Multimodal benzodiazapines+ opoid+ induction agent
Attenuate pressor response
Important for laryngoscopy and tracheal intubation
2% lignocaine 1-1.5mg/kg
Esmolol 50- 100 g/kg/min
During laryngoscopy catecholamine levels
Normally- 200- 2000 pg/ml
In pheo- 2000- 20,000 pg/ml



Neuromuscular blockade
Non depol neuromusc blocking drugs
DOC-Vecuronium
Suxamethonium- avoided causes fasciculations and rise
in intra abdominal pressure
Atracurium/ mivacurium- best avoided d. t release of
histamine
Cisatracurium/ rocuronium- safe cardio stable and least
histamine release
maintenance
Inhalational agent- isoflurane used extensively coz does
not sensitize the myocardium to catecholamines
Halothane undesirable arrhythmogenic properties
Sevoflurane used successfully (fast onset ..fast offset)
O.R
Have ready: IV phentolamine, IV NTP, IV esmolol
Other alternatives tried- MgSO4 ,40-60 mg/kg bolus
foll by 2 gms/hr
Very high uncontrolled BP- surgeons to stop
Ligation of adrenal vein- sudden hypotension
Rx hypotension with crystalloid +/- colloid 1
st
may need dopamine/ noradrenaline/ phenylephrine

Aim for CVP 12 or Wedge 15
Inotropes may not work!

Adverse perioperative effects
Large tumor size
Prolonged duration of surgery
Inc levels of preoperative urinary catecholamines and
catecholamine metabolites
Laparoscopic adrenalectomy.
If tumor < 8cm
Slow CO2 insufflation.. Not > 12 mm Hg


Postop
Post op ventilation / ICU stay- depends upon the
haemodynamic status. Preferably ICU stay for 24 hrs
Hypoglycemia post op d. t disinhibition of B cell
supression.. Inc insulin secretion
Glucose supplementation at end of surgery

Post op
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
5 yr survival- non malignant pheo- 95%
Malignant- < 50 %

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
131
I-MIBG or
111
indium-octreotide
depending on MIBG scan or octreoscan pick-up
Sensitize tumor with Carboplatin + 5-FU

Pheo & Pregnancy
Grave prognosis ,mortility: maternal - 48%, fetal 55%
Diagnosis with 24h urine collections and MRI
No stimulation tests, no MIBG if pregnant
Never spontaneous labour
1
st
& 2
nd
trimester (< 24 weeks):
Phenoxybenzamine + blocker prep
Resect tumor laprascopically
3
rd
trimester:
Phenoxybenzamine + blocker prep..2-3 wks
When 37 weeks: cesarian section followed by tumor
resection

Conclusion
Long term outlook very good
Managed by an experienced team of anaesthesiologist,
surgeon, endocrinologist &cardiologist
Principles of anaesthetic management
Good adrenergic blockade preop
Vigilent intraop monitoring and treatment of hyper/
hypotension
Post op ICU care
Antihypertensive for a prolonged period



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