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Pheochromocytoma

Pheochromocytoma. Dr. Atallah Al- Ruhaily. Pheochromocytoma. Catecholamine Physiology/Pathophysiology Clinical Presentation Epidemiology Signs & Symptoms Diagnosis Biochemical Localization Management Preoperative Operative Postoperative Pregnancy. Catecholamine Producing Tumors.

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Pheochromocytoma

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  1. Pheochromocytoma Dr. Atallah Al-Ruhaily

  2. Pheochromocytoma • Catecholamine Physiology/Pathophysiology • Clinical Presentation • Epidemiology • Signs & Symptoms • Diagnosis • Biochemical • Localization • Management • Preoperative • Operative • Postoperative • 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/chromaffintissue • Ganglioneuroma • Behave like paragangliomabiochemically

  5. 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 paragangliomabiochemically • Glomusjugulare 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 • 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, glomusjugulare: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

  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 • Catecholamine Physiology/Pathophysiology • Clinical Presentation • Epidemiology • Signs & Symptoms • Diagnosis • Biochemical • Localization • Management • Preoperative • Operative • Postoperative • 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 (> 3 drugs) • HTN present @ age < 20 or > 50 ? • Adrenal lesion found on imaging (ex. Incidentaloma)

  10. Pheo: Signs & Symptoms • The five P’s: • 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

  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 > 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, Carney’s Triad (Pheo, Gastric Leiomyoma, Pulm chondroma)

  17. Pheochromocytoma • Catecholamine Physiology/Pathophysiology • Clinical Presentation • Epidemiology • Signs & Symptoms • Diagnosis • Biochemical • Localization • Management • Preoperative • Operative • Postoperative • Pregnancy

  18. 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 591-890 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

  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 > 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

  22. Plasma Metanephrines • Not postural dependent: can draw normally • Secreted continuously by pheo • SEN 99% SPEC 89% • False Positive: acetaminophen

  23. Biochemical Tests: Summary

  24. 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

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

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

  27. MIBG Scan • 123I or 131I labelled metaiodobenzylguanidine • MIBG catecholamine precurosr taken up by the tumor • Inject MIBG, scan @ 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

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

  29. Pheochromocytoma • Catecholamine Physiology/Pathophysiology • Clinical Presentation • Epidemiology • Signs & Symptoms • Diagnosis • Biochemical • Localization • Management • Preoperative • Operative • Postoperative • Pregnancy

  30. 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

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

  32. Preop Preperation Regimens • Combined  +  blockade • Phenoxybenzamine • Selective 1-blocker (ex. Prazosin) • Propanolol • Metyrosine • Calcium Channel Blocker (CCB) • Nicardipine

  33. 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

  34. 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. • 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)

  35. 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

  36. Preop:  +  blockade • If BP still not cntrl despite  +  blockade • Add Prazosin to Phenoxybenzamine • Add CCB, ACE-I • Avoid diuretics as already ECFv contracted • Metyrosine

  37. 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

  38. Pheo: Rx of HTN Crisis • IV phentolamine • IV NTP • IV esmolol • IV labetalol – combined  +  blocker

  39. 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/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

  40. Preop: CCB • CCB • 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 Nicardipinegtt (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

  41. 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!

  42. O.R. • Anesthetic choice: • Enflurane or isoflurane: don’t sensitized myocardium to catecholamines • Halothane: may sensitize heart  arrhythmia • Laprascopic adrenalectomy if tumor < 8cm

  43. 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

  44. 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

  45. 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: • Phenoxybenzamine + blocker prep • When fetus large enough: cesarian section followed by tumor resection

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