Adrenal and

Pheochromocytoma
 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 Neuroblastoma

(Neuroblasts)

Chromaffin Cell Sympathetic Ganglion Cell

Intra-adrenal Extra-adrenal Ganglioneuroma

Pheochromocytoma
 Catecholamine Producing Tumors
 Pheochromocytoma
 Paraganglioma (extra-adrenal pheo)
 Originate in extra-adrenal sympathetic chain/chromaffin tissue
 Ganglioneuroma
 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 Metabolites
TH MAO, COMT
Tyrosine L-Dopa Dopamine Homovanillic acid
(HVA)
DBH

NorepinephrineCOMT Normetanephrine

PNMT MAO
COMT
Epinephrine Metaneprine
MAO
Tumor Secretion:
• Large Pheo: more metabolites
(metabolized within tumor before release) Vanillymandelic Acid
• Small Pheo: more catecholamines (VMA)
• 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
 Clinical Presentation
 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) 90%
 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
 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)

 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)
Diagnosis
 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% Spec 88%
 24h Utotal metanephrines Sen 76% Spec 94%
 24h Ucatechols + Utotal metanephrines Sen 90% Spec 98%
 24h UVMA Sen 63% 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
 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
 I or 131I labelled metaiodobenzylguanidine
123

 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
 18 F-fluorodeoxyglucose (FDG)
 6-[18F]-fluorodopamine
Management
 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
 Drug of choice
 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
 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 morning 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: CCB
 CCB
 Block norepi mediated Ca transport into vascular
smooth muscle
 Nicardipine: most commonly used agent
 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 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
 Surgical considerations
PHEOCHROMOCYTOMA
 MEN 2 (Bilateral and hyperplasia
precedes development of pheo.)
 If unil.: unil. adrenalectomy and close
F/U for devpt. Of metachronous lesions
1/3
 Bil. Adrenalectomy to prevent
metachronous leaving pt. With 10-
30%risk of addisonian crisis
 Surgical considerations
PHEOCHROMOCYTOMA
 Cortical sparing with risk of recurrence
of 25% in long term @10 yrs
 PHEOCHROMOCYTOMA/
Surgical Approaches
 1926 Charles Mayo
 1991 Snow et al. first transabdominal
 1992 Gagner :first lateral lap.adrenalectomy
 1995 Mercan posterior ,retrop.laparoscopic
 PHEOCHROMOCYTOMA/
Surgical Approaches
 6-8 cm as the limit for lap. Approach
– Pre-op or intraop. evidence of malignancy
 OPEN APPROACH:
– Malignant
– size
 1. Anterior (extraadrenal,bil.,mets.)
 2. Thoracoabdominal (large malignant)
 3. Lateral
 4. Posterior retroperitoneal
 PHEOCHROMOCYTOMA/
Surgical Approaches
 Very vascular :3 arterial supplies:
– • Inferior phrenic
– • Aorta
– • Renal artery
 Venous :single large
– right :short,IVC directly
– left: left renal vein
 PHEOCHROMOCYTOMA/
Surgical Approaches
 Mortality 0-3%
 Morbidity <5%
 Minimize tumor manipulation
 PHEOCHROMOCYTOMA/
FOLLOW UP CARE
 No reliable method to distinguish benign
from malignant: lifelong surveillance
 RR benign 6.5 %
 ½ of malignant have residual disease
 Recurrent pheo.may occur late as 20 yrs.
 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