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Pheochromocytoma

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Title: Pheochromocytoma


1
Pheochromocytoma
  • William Harper, MD, FRCPC
  • Endocrinology Metabolism
  • Assistant Professor of Medicine
  • McMaster University

2
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

3
Catecholamine Producing Tumors
Neural Crest
Neuroblastoma
Sympathoadrenal Progenitor Cell (Neuroblasts)
Chromaffin Cell
Sympathetic Ganglion Cell
Intra-adrenal Extra-adrenal Pheochromocytoma
Ganglioneuroma
4
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)

5
Catecholamine Producing Tumors
  • Cheodectoma
  • Carotid body, behave like paraganglioma
    biochemically
  • Glomus jugulare tumor
  • Intracranial branch of CN IX and X
  • Behave like paragangliomoa biochemically

6
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)
7
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

8
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

9
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)

10
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

11
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)

12
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)

13
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

14
Pheo Signs (metabolic)
  • Hypercalcemia
  • Associated MEN2 HPT
  • PTHrP secretion by pheo
  • Mild glucose intolerance
  • Lipolysis
  • Weight-loss
  • Ketosis gt VLDL synthesis (TG)

15
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

16
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)

17
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

18
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

19
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

20
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

21
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

22
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

23
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
24
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

25
Localization Imaging
  • CT abdomen
  • Adrenal pheo SEN 93-100
  • Extra-adrenal pheo SEN 90
  • MRI
  • gt SEN than CT for extra-adrenal pheo

26
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27
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

28
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

29
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30
Localization Nuclear medicine
  • MIBG
  • 111Indium-pentreotide
  • Some pheo have somatostatin receptors
  • PET
  • 18F-fluorodeoxyglucose (FDG)
  • 6-18F-fluorodopamine

31
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32
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

33
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

34
Preop W/up
  • CBC, lytes, creatinine, INR/PTT
  • CXR
  • EKG
  • Echo (r/o dilated CMY 2º catechols)

35
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!

36
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

37
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)

38
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

39
Preop ? ? blockade
  • If BP still not cntrl despite ? ? blockade
  • Add Prazosin to Phenoxybenzamine
  • Add CCB, ACE-I
  • Avoid diuretics as already ECFv contracted
  • Metyrosine

40
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

41
Pheo Rx of HTN Crisis
  • IV phentolamine
  • IV NTP
  • IV esmolol
  • IV labetalol combined ? ? blocker

42
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
43
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

44
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

45
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

46
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!

47
O.R.
  • Anesthetic choice
  • Enflurane or isoflurane dont sensitized
    myocardium to catecholamines
  • Halothane may sensitize heart ? arrhythmia
  • Laprascopic adrenalectomy if tumor lt 8cm

48
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

49
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

50
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
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