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Pheochromocytoma Dr. Atallah Al-Ruhaily
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Pheochromocytoma Catecholamine Physiology/Pathophysiology
Clinical Presentation Epidemiology Signs & Symptoms Diagnosis Biochemical Localization Management Preoperative Operative Postoperative Pregnancy
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Catecholamine Producing Tumors
Neural Crest Sympathoadrenal Progenitor Cell (Neuroblasts) Neuroblastoma 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
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Catecholamine Producing Tumors
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) 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 Tumor Secretion: Tyrosine L-Dopa Dopamine
TH MAO, COMT Tyrosine L-Dopa Dopamine Homovanillic acid (HVA) DBH COMT Norepinephrine Normetanephrine PNMT MAO Epinephrine COMT Metaneprine 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 MAO Vanillymandelic Acid (VMA) PNMT: Phenylethanolamine-N-Methyl Transferase COMT : Catechol-O-Methyl Ttransferase MAO: Mono-Amine Oxidase
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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 Catecholamine Physiology/Pathophysiology
Clinical Presentation Epidemiology Signs & Symptoms Diagnosis Biochemical Localization Management Preoperative Operative Postoperative Pregnancy
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Pheochromocytoma 0.01-0.1% of HTN population M = F
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 age < 20 or > 50 ? Adrenal lesion found on imaging (ex. Incidentaloma)
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Pheo: Signs & Symptoms The five P’s: The Classical Triad: Paroxysms
Pressure (HTN) 90% Pain (Headache) 80% Perspiration 71% Palpitation 64% Pallor 42% Paroxysms The Classical Triad: Pain (Headache), Perspiration, Palpitations Lack of all 3 virtually excluded diagnosis of pheo in a series of > 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 > 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, Carney’s Triad (Pheo, Gastric Leiomyoma, Pulm chondroma)
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Pheochromocytoma Catecholamine Physiology/Pathophysiology
Clinical Presentation Epidemiology Signs & Symptoms Diagnosis Biochemical Localization Management Preoperative Operative Postoperative 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 (> 2-3 fold elevation): 24h Ucatechols > 2-fold elevation ULN for total catechols 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
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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 > 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
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Plasma Metanephrines Not postural dependent: can draw normally
Secreted continuously by pheo SEN 99% SPEC 89% False Positive: acetaminophen
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Biochemical Tests: Summary
SEN SPEC Ucatechols 83% 88% Utotal metanephrines 76% 94% Ucatechols+metaneph 90% 98% UVMA 63% 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 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
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Localization: Imaging
CT abdomen Adrenal pheo SEN % Extra-adrenal pheo SEN 90% MRI > SEN than CT for extra-adrenal pheo
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Localization: Imaging
CT abdomen Adrenal pheo SEN % Extra-adrenal pheo SEN 90% MRI > SEN than CT for extra-adrenal pheo MIBG Scan SEN 77-90% SPEC %
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MIBG Scan 123I or 131I labelled metaiodobenzylguanidine
MIBG catecholamine precurosr taken up by the tumor Inject MIBG, 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
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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 Catecholamine Physiology/Pathophysiology
Clinical Presentation Epidemiology Signs & Symptoms Diagnosis Biochemical Localization Management Preoperative Operative Postoperative Pregnancy
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Pheo Management Prior to 1951, reported mortality for excision of pheochromoyctoma % HTN crisis, arrhythmia, MI, stroke Hypotensive shock Currently, mortality: % 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
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Preop: + blockade Start at least 10-14d preop Phenoxybenzamine
Allow sufficient time for ECFv re-expansion Phenoxybenzamine Special pharmacy access only (no DIN) Drug of choice Covalently binds -receptors (1 > 2) Start 10 mg po bid increase q2d by mg/d Increase until BP cntrl and no more paroxysms Maintenance mg/d (some need > 200 mg/d) Salt load: NaCl 600 mg od-tid as tolerated
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Preop: + blockade Phenoxybenzamine (cont’d) Selective 1-blockers
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 Synthetic inhibitor of Tyrosine Hydroxylase (TH)
L-Dopa Dopamine Synthetic inhibitor of Tyrosine Hydroxylase (TH) Special pharm access, no DIN Start 250 mg qid max 1 gm qid 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 DBH Norepinephrine PNMT Epinephrine
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Preop: CCB CCB Nicardipine: most commonly used agent
Block norepi mediated Ca transport into vascular smooth muscle Nicardipine: most commonly used agent 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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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: Laprascopic adrenalectomy if tumor < 8cm
Enflurane or isoflurane: don’t sensitized myocardium to catecholamines Halothane: may sensitize heart arrhythmia Laprascopic adrenalectomy if tumor < 8cm
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Postop Most cases can stop all BP meds postop
Postop hypotension: IV crystalloid HTN free: 5 years 74% 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 (< 24 weeks): Phenoxybenzamine + blocker prep Resect tumor ASAP laprascopically 3rd trimester: When fetus large enough: cesarian section followed by tumor resection
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