Pheochromocytoma.ppt

PheochromocytomaWilliam 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.Catecholamines Tyrosine TH Metabolites Dopamine DBH MAO. HVA Vanillymandelic Acid (VMA) . 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. HVA • Neuroblastoma: Dopamine.  insulin secretion 1:  HR/contractility. vasoconstriction. pupillary dilation 2:  presynaptic NE (clonidine). intestinal relaxation.  glycogenolysis 3:  lipolysis. bronchodilation.  lipolysis.  renin secretion 2: vasodilation. uterine contraction.  brown fat thermogenesis  Beta-Adrenergic Receptors    .Adrenergic Receptors  Alpha-Adrenergic Receptors   1: vasoconstriction. platelet aggregation. Pheochromocytoma 1. 2. 2. . 3. Epidemiology Signs & Symptoms Biochemical Localization Preoperative Operative Postoperative Pregnancy 3. 2. 2. 4. Diagnosis 1. Catecholamine Physiology/Pathophysiology Clinical Presentation 1. 4. Management 1. 5% of those screened M=F  3rd to 5th decades of life  Rare.1% of HTN population  Found in 0. 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. Incidentaloma) . 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). Palpitations Lack of all 3 virtually excluded diagnosis of pheo in a series of > 21. Perspiration.0000 patients . histamine.Pheo: Paroxysms. movement that increases intra-abdo pressure (lifting. ‘Spells’  10-60 min duration  Frequency: daily to monthly  Spontaneous  Precipitated:     Diagnostic procedures. straining) Micturition (bladder paraganlgioma) . glucagon. Contrast (I. unopposed -blockade.V.A. anesthesia induction. is OK) Drugs (opiods. I. metoclopramide) Strenuous exercise. ACTH. 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. Catechols induce dilated cardiomyopathy  systolic dysfn. 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.  Cardiac dysrhythmia & conduction defects . abdo pain. 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). cerebellar hemangioma. optic glioma Familial paraganglioma Familial pheo & islet cell tumor Other: Tuberous sclerosis. Sturge-Weber. MTC. HPT MEN 2b  50% Pheo (usually bilatl). Gastric Leiomyoma. MTC. retinoblastoma. mucosal neuroma. neurofibroma. Pulm chondroma) . renal/pancreas cysts NF1 (Von Recklinghausen's)  2% Pheo (50% if NF-1 and HTN)  Café-au-lait spots. ataxia-telangectgasia. Carney’s Triad (Pheo. marfanoid habitus Von Hippel-Landau  50% Pheo (usually bilat). nephroma. 2. Epidemiology Signs & Symptoms Biochemical Localization Preoperative Operative Postoperative Pregnancy 3. 2. 2. 3. Catecholamine Physiology/Pathophysiology Clinical Presentation 1.Pheochromocytoma 1. 4. 2. Management 1. 4. Diagnosis 1. . catecholamines.5 umol/d) 24h UVMA > 3-fold elevation • ULN 35 umol/d for most assays . +/-dopamine HPLC with electrochemical detection or mass spect 24h Ucatechols > 2-fold elevation • ULN for total catechols 591-890 nmol/d  Positive results (> 2-3 fold elevation):    24h Utotal metanephrines > 1.2 ug/d (6. vanillymandelic acid (VMA).24h Urine Collection  24h urine collection:   Creatinine. 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 . cocaine). amphetamines. propanolol. labetalol.24h Urine: False Positive  Drugs: TCAs. ethanol. raised ICP. sympathomimetics (cold remedies)  Hold these medications for 2 weeks!  Major physical stress (hypoglycemia. MAO-i. levodopa. stroke. ilicit drugs (opiods. methyldopa. etc.)  OSA . clonidine (withdrawal). 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 .8 nM (2000 pg/mL)  SEN 85% SPEC 80%  False positives: same as for 24h urine testing.Plasma Catecholamines  Drawn with patient fasting. supine. with an indwelling catheter in place > 30 min  Plasma total catechols > 11. also with diuretics. 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 Ucatechols Utotal metanephrines 83% 76% SPEC 88% 94% Ucatechols+metaneph UVMA Plasma catecholamines Plasma metanephrines 90% 63% 98% 94% 85% 99% 80% 89% . pheo patients won’t suppress their plasma norepi with clonidine May precipitate hypertensive crisis! Pheo patients.Suppression/Stimulation Testing  Clonidine suppression   May precipitate hypotensive shock! Unlike normals. will have a > 3x increase in plasma norepi with glucagon  Glucagon stimulation   . but not normals. Localization: Imaging  CT abdomen   Adrenal pheo SEN 93-100% Extra-adrenal pheo SEN 90% > SEN than CT for extra-adrenal pheo  MRI  . . 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% . reserpine. scan @ 24h. phenothiazines Must hold these medications for 4-6 wk prior to scan . 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.MIBG Scan  123I     or 131I labelled metaiodobenzylguanidine MIBG catecholamine precurosr taken up by the tumor Inject MIBG. . Localization: Nuclear medicine  MIBG  111Indium-pentreotide  Some pheo have somatostatin receptors 18F-fluorodeoxyglucose  PET   (FDG) 6-[18F]-fluorodopamine . . Management 1. 2. 2. Catecholamine Physiology/Pathophysiology Clinical Presentation 1. 2. . Epidemiology Signs & Symptoms Biochemical Localization Preoperative Operative Postoperative Pregnancy 3. 4. Diagnosis 1. 3.Pheochromocytoma 1. 2. 4. 7 %    Experienced & Coordinated team:  Endocrinologist. Swan-Ganz  Currently.Pheo Management  Prior to 1951. CVP line. mortality: 0 . arrhythmia. stroke Hypotensive shock Preoperative preperation. MI. EKG monitor. Anesthesiologist and Surgeon .50 %   HTN crisis.2. -blockade? New anesthetic techniques? • Anesthetic agents • Intraoperative monitoring: arterial line. reported mortality for excision of pheochromoyctoma 24 . INR/PTT  CXR  EKG  Echo (r/o dilated CMY 2º catechols) . creatinine. lytes.Preop W/up  CBC. Prazosin) Propanolol  Metyrosine  Calcium Channel Blocker (CCB)  Nicardipine  No Randomized Clinical Trials to compare various regimens! .Preop Preperation Regimens  Combined  +  blockade    Phenoxybenzamine Selective 1-blocker (ex. 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 > 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 > 200 mg/d) Salt load: NaCl 600 mg od-tid as tolerated . Preop:  +  blockade  Phenoxybenzamine (cont’d)   Side-effect: orthostasis with dosage required to normalized seated BP. reflex tachycardia Drawback: periop hypotension/shock unlikely to respond to pressor agent. 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)  Selective 1-blockers      . Prazosin. 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 . titrate to BP)  IV Nitroprusside (NTP)  Periop arrhythmia: IV esmolol  Periop Hypothension: IV crystalloid +/.colloid . then 2-5 mg IV q1-2h PRN or as continuous infusion (100 mg in 500cc D5W.Preop:  +  blockade  Meds given on AM of surgery  Periop HTN:  IV phentolamine – Short acting non-selective -blocker – Test dose 1 mg. Pheo: Rx of HTN Crisis  IV phentolamine  IV NTP  IV esmolol  IV labetalol – combined  +  blocker . no DIN PNMT  Start 250 mg qid  max 1 gm qid Epinephrine  Severe S/E’s: sedation. 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 . renal/chole stones. nausea/vomit. extrapyramidal. diarrhea. anxiety.Preop: Metyrosine Tyrosine  TH L-Dopa Dopamine Synthetic inhibitor of Tyrosine DBH Hydroxylase (TH) Norepinephrine  Special pharm access. 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 POD#1)  CCB  Block norepi mediated Ca transport into vascular smooth muscle  Nicardipine: most commonly used agent . 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 . Doxazosin) added to CCB if BP still high Periop arrythmia: IV esmolol Periop HTN: IV NTP Periop hypotension: • IV crystalloid or colloid • Dopamine.Preop: CCB  Cleveland Clinic:       Only 10% received phenoxybenzamine CCB 1st line agents as preop po med Selective 1-blockers (Prazosin. epi. phenylephrine . norepi. Terazosin.  Admit night before for overnight IV saline  Arterial line.O. IV esmolol Rx hypotension with crystalloid +/. CVP line  Known CHF: consider Swan-Ganz  Regardless of preop medications:     Have ready: IV phentolamine.colloid 1st Aim for CVP 12 or Wedge 15 Inotropes may not work! . IV NTP. EKG monitor.R. R.  Anesthetic choice:   Enflurane or isoflurane: don’t sensitized myocardium to catecholamines Halothane: may sensitize heart  arrhythmia  Laprascopic adrenalectomy if tumor < 8cm .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 . ACE-I. etc. Doxazosin) 1st line as less side-effects Phenoxybenzamine: more complete -blockade -blocker  CCB. Terazosin. Malignant  -blockade   Selective 1-blockers (Prazosin.  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: Unresectable. 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 Phenoxybenzamine + blocker prep When fetus large enough: cesarian section followed by tumor resection  3rd trimester:   .