Pheochromocytoma

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

Pheochromocytoma
1. 2.

Catecholamine Physiology/Pathophysiology Clinical Presentation
1. 2.

Epidemiology Signs & Symptoms Biochemical Localization Preoperative Operative Postoperative Pregnancy

3.

Diagnosis
1. 2.

4.

Management
1. 2. 3. 4.

Catecholamine Producing Tumors
Neural Crest Sympathoadrenal Progenitor Cell (Neuroblasts) Neuroblastoma

Chromaffin Cell

Sympathetic Ganglion Cell Ganglioneuroma

Intra-adrenal Extra-adrenal 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

glomus jugulare: Norepi ‡ Gangioneuroma: Norepi ‡ Malignant Pheo: Dopamine. HVA Vanillymandelic Acid (VMA) . HVA ‡ Neuroblastoma: Dopamine.Catecholamines Tyrosine TH Metabolites Dopamine DBH MAO. COMT L-Dopa Homovanillic acid (HVA) NorepinephrineCOMT 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 > Epi ‡ Familial Pheo: Epi > Norepi ‡ Paraganglioma: Norepi ‡ Cheodectoma.

pupillary dilation E2: q presynaptic NE (clonidine). platelet aggregation. intestinal relaxation. uterine contraction. o glycogenolysis F3: o lipolysis. o brown fat thermogenesis  Beta-Adrenergic Receptors    . o renin secretion F2: vasodilation. vasoconstriction. q insulin secretion F1: o HR/contractility.Adrenergic Receptors  Alpha-Adrenergic Receptors   E1: vasoconstriction. bronchodilation. o lipolysis.

4. 4. 2. 2. Epidemiology Signs & Symptoms Biochemical Localization Preoperative Operative Postoperative Pregnancy 3. 3. Catecholamine Physiology/Pathophysiology Clinical Presentation 1. 2.Pheochromocytoma 1. Diagnosis 1. . 2. Management 1.

investigate only if clinically suspicion:      Signs or Symptoms Severe HTN.01-0.Pheochromocytoma     0. HTN crisis Refractory HTN (> 3 drugs) HTN present @ age < 20 or > 50 ? Adrenal lesion found on imaging (ex.1% of HTN population  Found in 0.5% of those screened M=F 3rd to 5th decades of life Rare. Incidentaloma) .

0000 patients . Palpitations Lack of all 3 virtually excluded diagnosis of pheo in a series of > 21. Perspiration.Pheo: Signs & Symptoms  The five P¶s:      Pressure (HTN) Pain (Headache) Perspiration Palpitation Pallor 90% 80% 71% 64% 42% ‡ Paroxysms (the sixth P!)  The Classical Triad:   Pain (Headache).

straining) Micturition (bladder paraganlgioma) . Contrast (I. metoclopramide) Strenuous exercise.A.V. is OK) Drugs (opiods. movement that increases intra-abdo pressure (lifting. glucagon. anesthesia induction. I. histamine.Pheo: Paroxysms. ACTH. unopposed F-blockade. µSpells¶     10-60 min duration Frequency: daily to monthly Spontaneous Precipitated:     Diagnostic procedures.

Pheo: Hypotension! Hypo  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) .

abdo pain.Pheo: Signs & Symptoms   N/V. Catechols induce dilated cardiomyopathy systolic dysfn. severe constipation (megacolon) Chest-pains   Anxiety Angina/MI with normal coronaries: ± Catecholamine induced: o myocardial oxygen consumption or coronary vasospasm  CHF   HTN hypertrophic cardiomyopathy diastolic 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: µRule 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 .

cerebellar hemangioma. ataxia-telangectgasia. Pulm chondroma) . MTC. retinoblastoma. optic glioma Familial paraganglioma Familial pheo & islet cell tumor Other: Tuberous sclerosis. Sturge-Weber.Familial Pheo        MEN 2a  50% Pheo (usually bilateral). MTC. renal/pancreas cysts NF1 (Von Recklinghausen's)  2% Pheo (50% if NF-1 and HTN)  Café-au-lait spots. mucosal neuroma. marfanoid habitus Von Hippel-Landau  50% Pheo (usually bilat). Carney¶s Triad (Pheo. HPT MEN 2b  50% Pheo (usually bilatl). Gastric Leiomyoma. nephroma. neurofibroma.

Pheochromocytoma 1. 2. Catecholamine Physiology/Pathophysiology Clinical Presentation 1. 4. 4. Management 1. Epidemiology Signs & Symptoms Biochemical Localization Preoperative Operative Postoperative Pregnancy 3. Diagnosis 1. 3. 2. 2. 2. .

5 umol/d) 24h UVMA > 3-fold elevation ‡ ULN 35 umol/d for most assays .24h Urine Collection  24h urine collection: Creatinine. vanillymandelic acid (VMA). catecholamines.2 ug/d (6. +/-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. metanephrines.

24h Urine Collection  Test     Characteristics: 24h Ucatechols Sen 83% 24h Utotal metanephrines Sen 76% 24h Ucatechols + Utotal metanephrines Sen 90% 24h UVMA Sen 63% Spec 88% Spec 94% Spec 98% Spec 94%  Sensitivity increased if 24h urine collection begun at onset of a paroxysm .

methyldopa. stroke.24h Urine: False Positive     Drugs: TCAs. ilicit drugs (opiods. ethanol. clonidine (withdrawal). amphetamines. labetalol. cocaine). MAO-i. sympathomimetics (cold remedies) Hold these medications for 2 weeks! Major physical stress (hypoglycemia. etc. raised ICP. levodopa.) OSA . propanolol.

Plasma Catecholamines     Drawn with patient fasting. 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 . 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. supine.

Plasma Metanephrines postural dependent: can draw normally  Secreted continuously by pheo  SEN 99% SPEC 89%  False Positive: acetaminophen  Assay not readily available in Canada  Not .

Biochemical Tests: Summary SEN Ucatechols Utotal metanephrines Ucatechols+metaneph UVMA Plasma catecholamines Plasma metanephrines SPEC 88% 94% 98% 94% 80% 89% 83% 76% 90% 63% 85% 99% .

Suppression/Stimulation Testing  Clonidine suppression   May precipitate hypotensive shock! Unlike normals. but not normals. pheo patients won¶t suppress their plasma norepi with clonidine  Glucagon   stimulation May precipitate hypertensive crisis! Pheo patients. will have a > 3x increase in plasma norepi with glucagon .

Localization: Imaging  CT abdomen   Adrenal pheo SEN 93-100% Extra-adrenal pheo SEN 90% > SEN than CT for extra-adrenal pheo  MRI  .

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Localization: Imaging  CT abdomen   Adrenal pheo SEN 93-100% Extra-adrenal pheo SEN 90% > SEN than CT for extra-adrenal pheo  MRI   MIBG  Scan SEN 77-90% SPEC 95-100% .

72h Lugol¶s 1 gtt tid x 9d (from 2d prior until 7d after MIBG injection to protect thyroid) False negative scan:   Drugs: Labetalol. TCAs. 48h. phenothiazines Must hold these medications for 4-6 wk prior to scan . reserpine. scan @ 24h.MIBG Scan  123I     or 131I labelled metaiodobenzylguanidine MIBG catecholamine precurosr taken up by the tumor Inject MIBG.

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Localization: Nuclear medicine  MIBG  111Indium-pentreotide  Some pheo have somatostatin receptors 18F-fluorodeoxyglucose  PET   (FDG) 6-[18F]-fluorodopamine .

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. 2. 3. 4. Catecholamine Physiology/Pathophysiology Clinical Presentation 1. Diagnosis 1. Management 1. 2. 4. Epidemiology Signs & Symptoms Biochemical Localization Preoperative Operative Postoperative Pregnancy 3. 2. 2.Pheochromocytoma 1.

Anesthesiologist and Surgeon .50 %   HTN crisis. arrhythmia.Pheo Management  Prior to 1951. EKG monitor. CVP line. MI. stroke Hypotensive shock Preoperative preperation.2. Swan-Ganz  Currently. reported mortality for excision of pheochromoyctoma 24 .7 %    Experienced & Coordinated team:  Endocrinologist. mortality: 0 . E-blockade? New anesthetic techniques? ‡ Anesthetic agents ‡ Intraoperative monitoring: arterial line.

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

Preop Preperation Regimens  Combined E + F blockade    Phenoxybenzamine Selective E1-blocker (ex. Prazosin) Propanolol   Metyrosine Calcium Channel Blocker (CCB)  Nicardipine  No Randomized Clinical Trials to compare various regimens! .

Preop: E + F 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 E-receptors (E1 > E2) 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 .

reflex tachycardia Drawback: periop hypotension/shock unlikely to respond to pressor agent. Prazosin.Preop: E + F blockade  Phenoxybenzamine (cont¶d)   Side-effect: orthostasis with dosage required to normalized seated BP. Doxazosin Some experience with Prazosin for Pheo preop prep Not routinely used as incomplete E-blockade Less orthostasis & reflex tachycardia then phenoxybenzamine Used more for long-term Rx (inoperable or malignant pheo)  Selective E1-blockers      . Terazosin.

Preop: E + F blockade  F-blockade     Used to control reflex tachycardia and prophylaxis against arrhythmia during surgery Start only after effective E-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: E + F blockade  If BP     still not cntrl despite E + F blockade Add Prazosin to Phenoxybenzamine Add CCB. ACE-I Avoid diuretics as already ECFv contracted Metyrosine .

Preop: E + F blockade   Meds given on AM of surgery Periop HTN:  IV phentolamine ± Short acting non-selective E-blocker ± Test dose 1 mg. titrate to BP)  IV Nitroprusside (NTP)   Periop arrhythmia: IV esmolol Periop Hypothension: IV crystalloid +/. then 2-5 mg IV q1-2h PRN or as continuous infusion (100 mg in 500cc D5W.colloid .

Pheo: Rx of HTN Crisis  IV phentolamine  IV NTP  IV esmolol  IV labetalol ± combined E + F blocker .

renal/chole stones. no DIN PNMT Start 250 mg qid max 1 gm qid Epinephrine Severe S/E¶s: sedation. anxiety. nausea/vomit.Preop: Metyrosine Tyrosine       TH L-Dopa Dopamine Synthetic inhibitor of Tyrosine DBH Hydroxylase (TH) Norepinephrine Special pharm access. galactorrhea Alone may insufficiently cntrl BP and reported HTN crises during pheo operation Restrict use to inoperable/malignant pheo or as adjunct to E + F blockade or other preop prep . diarrhea. extrapyramidal.

479 cc POD#1)  CCB  Block norepi mediated Ca transport into vascular smooth muscle  Nicardipine: most commonly used agent .Preop: CCB  Cleveland Clinic Experience     Only 6 cardiovascular complications All occurred in patients with preop E-blockade 30% received no medications preop if no HTN Patients not receiving phenoxybenzamine required less fluids (956 cc intraop.

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 E-blocked .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.

epi. phenylephrine . Terazosin.Preop: CCB  Cleveland    Clinic:    Only 10% received phenoxybenzamine CCB 1st line agents as preop po med Selective E1-blockers (Prazosin. norepi. Doxazosin) added to CCB if BP still high Periop arrythmia: IV esmolol Periop HTN: IV NTP Periop hypotension: ‡ IV crystalloid or colloid ‡ Dopamine.

CVP line  Known CHF: consider Swan-Ganz  Regardless of preop medications:     Have ready: IV phentolamine. IV NTP.O.R. EKG monitor.  Admit night before for overnight IV saline  Arterial line.colloid 1st Aim for CVP 12 or Wedge 15 Inotropes may not work! . IV esmolol Rx hypotension with crystalloid +/.

 Anesthetic  choice:  Enflurane or isoflurane: don¶t sensitized myocardium to catecholamines Halothane: may sensitize heart arrhythmia  Laprascopic adrenalectomy if tumor < 8cm .R.O.

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 .

Doxazosin) 1st line as less side-effects Phenoxybenzamine: more complete E-blockade    F-blocker CCB. Terazosin. ACE-I.Pheo: Unresectable. 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 . Malignant  E-blockade   Selective E1-blockers (Prazosin.

no MIBG if pregnant 1st & 2nd trimester (< 24 weeks):   Phenoxybenzamine + Fblocker prep Resect tumor ASAP laprascopically Phenoxybenzamine + Fblocker prep When fetus large enough: cesarian section followed by tumor resection  3rd trimester:   .Pheo & Pregnancy    Diagnosis with 24h urine collections and MRI No stimulation tests.

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