Pheochromocytoma

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Pheochromocytoma

• William Harper, MD, FRCPC
• Endocrinology Metabolism
• Assistant Professor of Medicine
• McMaster University

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Pheochromocytoma

1. Catecholamine Physiology/Pathophysiology
2. Clinical Presentation
3. Epidemiology
4. Signs Symptoms
5. Diagnosis
6. Biochemical
7. Localization
8. Management
9. Preoperative
10. Operative
11. Postoperative
12. Pregnancy

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Catecholamine Producing Tumors
Neural Crest
Neuroblastoma
Sympathoadrenal Progenitor Cell (Neuroblasts)
Chromaffin Cell
Sympathetic Ganglion Cell
Intra-adrenal Extra-adrenal Pheochromocytoma
Ganglioneuroma
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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)

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Catecholamine Producing Tumors

• Cheodectoma
• Carotid body, behave like paraganglioma
  biochemically
• Glomus jugulare tumor
• Intracranial branch of CN IX and X
• Behave like paragangliomoa biochemically

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

• Tumor Secretion
• Large Pheo more metabolites
• (metabolized within tumor before release)
• Small Pheo more catecholamines
• Sporadic Pheo Norepi gt Epi
• Familial Pheo Epi gt Norepi
• Paraganglioma Norepi
• Cheodectoma, glomus jugulare Norepi
• Gangioneuroma Norepi
• Malignant Pheo Dopamine, HVA
• Neuroblastoma Dopamine, HVA

Vanillymandelic Acid (VMA)
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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

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Pheochromocytoma

1. Catecholamine Physiology/Pathophysiology
2. Clinical Presentation
3. Epidemiology
4. Signs Symptoms
5. Diagnosis
6. Biochemical
7. Localization
8. Management
9. Preoperative
10. Operative
11. Postoperative
12. Pregnancy

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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 (gt 3 drugs)
• HTN present _at_ age lt 20 or gt 50 ?
• Adrenal lesion found on imaging (ex.
  Incidentaloma)

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Pheo Signs Symptoms

• The five Ps
• 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 gt 21,0000 patients

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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)

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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)

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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

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Pheo Signs (metabolic)

• Hypercalcemia
• Associated MEN2 HPT
• PTHrP secretion by pheo
• Mild glucose intolerance
• Lipolysis
• Weight-loss
• Ketosis gt VLDL synthesis (TG)

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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

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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, Carneys Triad (Pheo,
  Gastric Leiomyoma, Pulm chondroma)

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Pheochromocytoma

1. Catecholamine Physiology/Pathophysiology
2. Clinical Presentation
3. Epidemiology
4. Signs Symptoms
5. Diagnosis
6. Biochemical
7. Localization
8. Management
9. Preoperative
10. Operative
11. Postoperative
12. Pregnancy

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24h Urine Collection

• 24h urine collection
• Creatinine, catecholamines, metanephrines,
  vanillymandelic acid (VMA), /-dopamine
• HPLC with electrochemical detection or mass spect
• Positive results (gt 2-3 fold elevation)
• 24h Ucatechols gt 2-fold elevation
• ULN for total catechols 591-890 nmol/d
• 24h Utotal metanephrines gt 1.2 ug/d (6.5 umol/d)
• 24h UVMA gt 3-fold elevation
• ULN 35 umol/d for most assays

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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

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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

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Plasma Catecholamines

• Drawn with patient fasting, supine, with an
  indwelling catheter in place gt 30 min
• Plasma total catechols gt 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

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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

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Biochemical Tests Summary
SEN SPEC
Ucatechols 83 88
Utotal metanephrines 76 94
Ucatecholsmetaneph 90 98
UVMA 63 94
Plasma catecholamines 85 80
Plasma metanephrines 99 89
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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 gt 3x
  increase in plasma norepi with glucagon

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Localization Imaging

• CT abdomen
• Adrenal pheo SEN 93-100
• Extra-adrenal pheo SEN 90
• MRI
• gt SEN than CT for extra-adrenal pheo

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Localization Imaging

• CT abdomen
• Adrenal pheo SEN 93-100
• Extra-adrenal pheo SEN 90
• MRI
• gt SEN than CT for extra-adrenal pheo
• MIBG Scan
• SEN 77-90 SPEC 95-100

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MIBG Scan

• 123I or 131I labelled metaiodobenzylguanidine
• MIBG catecholamine precurosr taken up by the
  tumor
• Inject MIBG, scan _at_ 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

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Localization Nuclear medicine

• MIBG
• 111Indium-pentreotide
• Some pheo have somatostatin receptors
• PET
• 18F-fluorodeoxyglucose (FDG)
• 6-18F-fluorodopamine

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Pheochromocytoma

1. Catecholamine Physiology/Pathophysiology
2. Clinical Presentation
3. Epidemiology
4. Signs Symptoms
5. Diagnosis
6. Biochemical
7. Localization
8. Management
9. Preoperative
10. Operative
11. Postoperative
12. Pregnancy

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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

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Preop W/up

• CBC, lytes, creatinine, INR/PTT
• CXR
• EKG
• Echo (r/o dilated CMY 2º catechols)

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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!

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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 gt ?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 gt 200 mg/d)
• Salt load NaCl 600 mg od-tid as tolerated

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Preop ? ? blockade

• Phenoxybenzamine (contd)
• 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)

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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

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Preop ? ? blockade

• If BP still not cntrl despite ? ? blockade
• Add Prazosin to Phenoxybenzamine
• Add CCB, ACE-I
• Avoid diuretics as already ECFv contracted
• Metyrosine

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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

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Pheo Rx of HTN Crisis

• IV phentolamine
• IV NTP
• IV esmolol
• IV labetalol combined ? ? blocker

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Preop Metyrosine
TH
Tyrosine
L-Dopa
Dopamine

• Synthetic inhibitor of Tyrosine
• Hydroxylase (TH)
• Special pharm access, no DIN
• 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

DBH
Norepinephrine
PNMT
Epinephrine
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Preop CCB

• Cleveland Clinic Experience
• 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 POD1)
• CCB
• Block norepi mediated Ca transport into vascular
  smooth muscle
• Nicardipine most commonly used agent

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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

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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

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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!

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O.R.

• Anesthetic choice
• Enflurane or isoflurane dont sensitized
  myocardium to catecholamines
• Halothane may sensitize heart ? arrhythmia
• Laprascopic adrenalectomy if tumor lt 8cm

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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

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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

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Pheo Pregnancy

• Diagnosis with 24h urine collections and MRI
• No stimulation tests, no MIBG if pregnant
• 1st 2nd trimester (lt 24 weeks)
• Phenoxybenzamine ?blocker prep
• Resect tumor ASAP laprascopically
• 3rd trimester
• Phenoxybenzamine ?blocker prep
• When fetus large enough cesarian section
  followed by tumor resection