Pheochromocytoma (1 of 6)

1 Patient presents w/ signs & symptoms of pheochromocytoma

No DIAGNOSIS Yes Is pheochromocytoma conﬁ rmed?

ALTERNATIVE DIAGNOSIS A Pharmacological therapy • Liberal salt intake • Alpha-adrenergic blockade x 10-14 days - 1st-line agent: Phenoxybenzamine • Beta-blocker - Only after alpha blockade has been induced • Calcium channel blocker - To be given w/ an alpha blocker

3 LOCALIZATION OF TUMOR

A Pharmacological therapy • Long-term alpha-adrenergic blockade PREOP - w/ or w/o Calcium channel blockers No EVALUATION • Metirosine Is tumor resectable? - If alpha blockade is insuﬃ cient in controlling symptoms

Yes

B Surgery • Laparoscopic • Open • Laparoscopic assisted

C © MIMS FOLLOWUP

Not all products are available or approved for above use in all countries. Speciﬁ c prescribing information may be found in the latest MIMS.

B1 © MIMS 2019 PHEOCHROMOCYTOMA • • • • • Metanephrine Plasma • • • • • Symptoms Other • • • w/≥1ofthefollowing: present ofpatients Majority • • • • sample: urine from aremeasured 2ofthefollowing at if least improved is Accuracy • TestsUrine Biochemical • • • • 24-Hr Urine Sample - Pharmacologic tests may be helpful indiﬃ helpful may be Pharmacologic tests - cult cases Tests attacks toexclude during diagnosis repeated tobe may need collection &after &refrigerate during urine Acidify patient &norecent contrast toradiographic not takingmedication If possible, media isat exposure rest, - concentration totalcathecholamines donewhen plasma Maybe butnotdiagnostic iselevated - test Clonidine suppression conﬁ levels plasma Elevated therm diagnosis - excludes the levels diagnosis plasma Normal - predisposition More suitable patients forhighrisk w/ahereditary - ofchoice test Diagnostic extractions doneinthe sameposition w/patient w/subsequent obtained measurement insupineposition, shouldbe metanephrine forplasma Blood Evaluation usingliquid chromatography chromatography methods w/mass laboratory over ispreferred - symptoms Cardiac - Orthostatic hypotension loss Mild-moderate wt - rate metabolic Increased Very highBPusually w/tachycardia - Pallormay occur - apprehension, palpitations, orabdomen chest pain,N/V sweating, w/headache, Associated - hr) inlength (eg Usually butvariable min-several sudden inonset - Occurs inhalfofpatients - Paroxysmal which disorder, suggest symptoms seizure attacks orhyperventilation anxiety (MI) infarction encephalopathy, hypertensive w/ malignant hypertension, crisis Hypertensive ormyocardial dissection aortic excessive &/orpalpitations sweating w/headaches, associated May be - resistant tostandardHypertension antihypertensive treatment 10% ofpatients are asymptomatic Usually youngtomid-adultlife occurs during - occur at can any age Pheochromocytoma - Glucagon stimulation test pheochromocytoma 50%suggests by Failure levels norepinephrine tosuppress - - - Unconjugated catecholamines (free) forpheochromocytoma at risk inthose preferred low May be - Alternative forexcluding pheochromocytoma Rarely used - pheochromocytoma toglucagon signify inresponse levels innorepinephrine A3-foldrise - Cardiomyopathy - changes ECG - - - Metanephrine/Normetanephrine - Cr Full 24-hrsample ispreferred done when sample patient acrisis ofurine shouldbe orduring Analysis hypertensive issymptomatic eg -

May distinguish elevated norepinephrine levels secondary to sympathetic nerves vs true pheochromocytoma true vs tosympathetic nerves secondary levels norepinephrine elevated May distinguish arrhythmias Sinus sinus tachycardia, &other bradycardia sympathetic reﬂexes volume & dulled plasma decreased from Results high are are either high but catecholamines levels or only moderately normal metanephrine whenPerformed plasma disease artery of coronary inthe may absenceAcute MIorangina occur even Normal range: 590-885nmol/24hr(100-150mcg/24hr) range: Normal >1480 nmol/24 hr (>250 mcg/24 hr), or 2-fold elevation from normal level normal from >1480nmol/24hr(>250mcg/24hr),or2-foldelevation range: Diagnostic 7micromol/24 hr(1.3 mg/24hr) range: ofnormal limit Upper is present adrenal lesion (MEN) neoplastics highifmultiple &may endocrine be measured be Epinephrine shouldalso Normetanephrine (>900 mcg/24 hr); Metanephrine (>400 mcg/24hr) (>900mcg/24hr);Metanephrine Normetanephrine range: Diagnostic Cl should be measured to assess adequacy ofcollection adequacy toassess measured shouldbe

© MIMS 1 SIGNS & SYMPTOMS OF PHEOCHROMOCYTOMA Pheochromocytoma (2of6) 2 DIAGNOSIS B2 • • • • • • • Hypokalemia renal failure rhabdomyolysis w/ myoglobinuric occasionally Polyuria, sedimentationFever, rate (ESR) erythrocyte elevated Hypercalcemia volume plasma todecreased secondary hematocrit Elevated Carbohydrate intolerance edema pulmonary w/noncardiogenicMulti-organ failure system © MIMS 2019 PHEOCHROMOCYTOMA • Scintigraphy (MIBG) Metaiodobenzylguanidine pheochromocytoma localizing for 1st-line procedures as notrecommended are Functional techniques imaging Functional Imaging • • Aortography Abdominal • • • • • • CT • • • • Imaging Resonance Magnetic Anatomic Imaging • • Scintigraphy Receptor Somatostatin • • • • • • TomographyPositron Emission Imaging (PET) • • • • Phenoxybenzamine • Blockade Alpha-Adrenergic May use I May use Alpha-adrenergic completed must attempting before blockade be aortography extraadrenal tumors alarge inthe by abdomen since are toidentify aberrant usuallysupplied artery they used May be pheochromocytoma tolocate method the useful most as consider Some CT - w/contrast aggravate can orprecipitate crisis CT forsmall thoracic preferred tumorsSpiral CT &neck chest areas); these shouldvisualize tumorsExtraadrenal (initalCT w/inthe abdomen &pelvis of≥1-2cm pheochromocytoma of≥0.5-1cmormetastatic adrenal pheochromocytoma Detects - assessment &metastatic localization provide Both - are 1st-line &MRI scan tools diagnostic CT at the pharmacologically Patient sametime prepared be can - adrenal Maybe orextra-adrenal (paraganglioma) - undertaken shouldbe metastases forpossible &search Once tumor patient localization isdiagnosed Initial evaluation for children, pregnant women or in cases ofcontrast allergy forchildren, pregnant women orincases Initial evaluation motion-induced artifacts andrespiratory cardiac Reduces - pheochromocytoma juxtavascular juxtacardiac, intracardiac, Detect - extraadrenal inthe lesions abdomen Identify intraadrenal lesions Identify - Low sensitivity Low tumors than tumors better primary/benign malignant/metastatic Detects isexpensive Procedure centers availability amongvarious Limited scintigraphy lesions metastatic forpatients w/known MIBG over Preferred accurate lesions Provides the ofmetastatic information regarding number &location Unlikely delays inscintigraphy - outimmediately iscarried Imaging spatial resolution Advantages andsuperior include radiation low exposure is>10cmindiameter are oriffoundpheochromocytoma negative, results when imaging abdominal Indicated anatomy w/distorted in unusual orinareas location tumors w/ﬁ pheochromocytoma, recurrent ormetastatic indetecting Useful tumors tumors, extranodal brosis, - Used to control the hypertension caused by excessive catecholamine release by pheochromocytoma tocontrol by excessive by Used release catecholamine caused the hypertension - Eﬀ ects: alpha-adrenergic ofthe blocker irreversible inthe alphareceptors Powerful Action: muscles smooth First-line complications tominimize therapy tosurgery used prior S

- CT scan is preferred over MRI as 1st-line diagnostic tool for imaging of the thorax, abdomen & pelvic area abdomen &pelvic 1st-line ofthe forimaging as thorax, MRI over ispreferred tool diagnostic scan CT bilateral orextra-adrenal neuroﬁ disease for von Hippel-Lindau Look bromatosis inCT seen &radiation,dyes &forpatients w/artifacts patients w/ contraindications for contrast & neck, of tumors in the skull base for detection best is used MRI I can 123 is superior toI issuperior Oral administration results in an onset of action w/in a few hr & persists forupto3-4days hr&persists ofactionw/inafew inanonset Oraladministration results 131 andI

131 Not all products are available or approved for above use in all countries. all in use above for approved or available are products all Not , but is not approved by USFDA by , butisnotapproved Specifi c prescribing information may be found in the latest MIMS. latest the in found be may information Specific prescribing A 2 PHARMACOLOGICAL THERAPY LOCALIZATION OF TUMOR Pheochromocytoma (3of6) B3 or multiple endocrine neoplasia type 2 (MEN-II) if 2 (MEN-II) type neoplasia or multiple endocrine © MIMS 2019 PHEOCHROMOCYTOMA 1 Many selective alpha Many selective • • • • • • • • • • Alpha Selective (Cont’d) Blockade Alpha-Adrenergic • • • (Metyrosine) Metirosine • • • • Blockers Channel Calcium • • • • • Beta-Blockers • • • inheritance of risk possible andtoidentify mutationscausing germ-line mutations, that diseases, may tometastatic lead presence to determine of disease- considered in should patientsbe testing w/ pheochromocytoma Genetic reappear ifsymptoms ormore yrly often measured excretionCatecholamine shouldbe complete Ensures tumor removal - surgery excretion catecholamine 1-2wkafter Measure - the procedure during surgical crisis & prevent hypertensive management pharmacologic Preoperative adrenergic to control involves pressure blockade alpha&beta blood disease eentire toprevent recurrence removed oflocal must gland&the tissues surrounding be - surgery potentially malignant during as regarded shouldbe pheochromocytoma Each It diffi ismicroscopically ismalignant ifpheochromocytoma cult todetermine centers inexperienced performed Should be Treatment ofpheochromocytoma ofchoice cases formost ofalpha blockade Selective Action: Eg Doxazosin Should be used ifother agents used Should are ineff be marked be will orwhen tumor destruction ective Eff ects: the by tumor ofcatecholamines hydroxylase synthesis which tyrosine inhibits Inhibits Action: Eff ects: channels calcium ionfl slow toprevent calcium Blocks Action: intoow the cell peri-operatively function add-ontreatment as Used toalpha-adrenergic improve tofurther cardiovascular blockers receptor Amlodipine Eg Nifedipine, are usuallysuffi doses Low cient arrhythmias inpreventing catecholamine-induced Assist - Eff ects: at antagonists receptors beta-adrenergic ofcatecholamines Competitive Action: inBPmay occur paradox W/oalphablockade increase - induced been has Administer alphablockade onlyafter Eg Propranolol, Atenolol ispresent ifpheochromocytoma crisis pressor Prevent serious - tolerated than Phenoxybenzamine Better - workup isongoing whilepheochromocytoma totreat hypertension used mayMay also be paroxysms totreat individual used May be Eff ects:

depletion fl w/increased diet A high-sodium uid intake pre-op isrecommended toprevent post-operative volume Limited use in pheochromocytoma, Phenoxybenzamine ismore eff inpheochromocytoma, use Limited ective Simplifi chronices management Vasodilatation, pressure resistance peripheral &blood afterload, reduced totreat tachycardiaUsed that may w/alphablockade develop 1 -Antagonists 1 © MIMS the forspecifi latest MIMS antagonists see are available. Please c formulations. Not all products are available or approved for above use in all countries. all in use above for approved or available are products all Not A Specifi c prescribing information may be found in the latest MIMS. latest the in found be may information Specific prescribing PHARMACOLOGICAL THERAPY (CONT’D) 1 1 Pheochromocytoma (4of6) -adrenoreceptors C B FOLLOW-UP SURGERY B4 © MIMS 2019 PHEOCHROMOCYTOMA 1 Many beta-blockers are available. Please see the forspecifi latest MIMS see are available.Many Please beta-blockers c formulations. Phentolamine Derivative Imidazoline (Doxazosine) Doxazosin Antagonist Alpha-Adrenoreceptor Propranolol Drug Drug Products listed above may not be mentioned in the disease management chart but have been have but chart management disease the in mentioned be not may above listed Products placed here based on indications listed in regional manufacturers’ product information. product manufacturers’ regional in listed indications on based here placed & non-elderly adults w/ normal renal & hepatic function unless otherwise stated. otherwise unless function &hepatic renal w/ normal adults & non-elderly All dosage recommendations are for non-pregnant & non-breastfeeding women, women, &non-breastfeeding non-pregnant for are recommendations dosage All © MIMS 16 mg/day dose: Max 24hrly 2-4 mgPO dose: Maintenance additional 1-2wk 24hrly for 2 mgPO to dose May increase 24 hrly x 1-2 wk 1mgPO dose: Initial to control rate pulse needed as May increase 6-8hrly 10 mgPO dose: Initial IV as needed as IV During surgery: to surgery 1-2hrprior 1 mgIV/IM Childn: needed as May repeat 2-5 mgIV Adult: pheochromocytoma: in For hypertension Not all products are available or approved for above use in all countries. all in use above for approved or available are products all Not Specifi c prescribing information may be found in the latest MIMS. latest the in found be may information Specific prescribing Dosage Dosage OTHER ANTIHYPERTENSIVES Pheochromocytoma (5of6) 1mg Dosage Guidelines BETA-BLOCKER • • Instructions Special • Reactions Adverse • Instructions Special • • Reactions Adverse • • Instructions Special • Reactions Adverse for 24 hr after initiation oftherapyfor 24hrafter tasks hazardous Avoid orperforming todriving prior use orthostatic hypotension prostatic carcinoma, Use w/caution inpatients w/renal/hepatic impairment, polyuria) dysfunction, Other eff sexual muscle headache, cramps, (fatigue, ects infl(dyspnea, epistaxis); rhinitis, symptoms, uenza-like arrhythmia); efforthostatic hypotension, Resp ects effCV (chest palpitation, pain,hypotension, ects GI eff nausea); mouth, pain,diarrhea, abdominal (dry ects effNeurologic hypertonia); disorders, kinetic (ataxia, ects DM (COPD), disease pulmonary chronic obstructive Use w/caution inpatients w/asthma, May interfere w/carbohydrate rash &lipidmetabolism, eff fatigue) (bronchospasm, ects eff disturbances); sleep Other (depression, dizziness, ects CNS failure); heart block, heart disorders: CV preexisting effCV inpatients hypotension w/ (bradycardia, ects coronary/cerebral arteriosclerosis inpatientsContraindicated w/renal impairment, Monitor BPwhileontherapy congestion) eff (flects nasal dizziness, weakness, sweating, ushing, GIeffpain, arrhythmias); Other N/V); (diarrhea, ects effCV anginal orthostatic hypotension, (tachycardia, ects B5 1 Remarks Remarks © MIMS 2019 PHEOCHROMOCYTOMA (Metyrosine) Metirosine Phenoxybenzamine Peripheral VasodilatorsOther Drug Drug Products listed above may not be mentioned in the disease management chart but have been have but chart management disease the in mentioned be not may above listed Products placed here based on indications listed in regional manufacturers’ product information. product manufacturers’ regional in listed indications on based here placed & non-elderly adults w/ normal renal & hepatic function unless otherwise stated. otherwise unless function &hepatic renal w/ normal adults & non-elderly All dosage recommendations are for non-pregnant & non-breastfeeding women, women, &non-breastfeeding non-pregnant for are recommendations dosage All © MIMS ≥2 hr over NaCl 0.9%infused in200ml 1 mg/kg/day IV Adult: pheochromocytoma: in cover Operative 6-8 hrly 0.4-1.2 mg/kg/day PO Maintenance: 0.2 mg/kgincrements by May increase 24 hrly 0.2mg/kgPO dose: Initial Childn: ifneeded doses divided 1-2 mg/kg/day in2 to slowly May increase 12-24 hrly 10mgPO dose: Initial Adult: pheochromocytoma: in For hypertension Administer for 5-7days Pre-op management: 4g/day dose: Max 250-500 mg/day patient by response on based dose Increase 6hrly 250 mgPO dose: Initial Not all products are available or approved for above use in all countries. all in use above for approved or available are products all Not Specifi c prescribing information may be found in the latest MIMS. latest the in found be may information Specific prescribing OTHER ANTIHYPERTENSIVES(CONT’D) Please see the end of this section for the reference list. reference the for section this of end the see Please TYROSINE HYDROXYLASE INHIBITOR Dosage Dosage Pheochromocytoma (6of6) Dosage Guidelines • • Instructions Special • Reactions Adverse • • • • Instructions Special • Reactions Adverse B6 of upright &supineBP monitoring w/close slowly increased shouldbe Doses dangerous &inpatientsinfections where inBPcould fall be renal impairment, respiratory cerebrovascular disease, disease, Use w/caution inpatients w/CV Other eff fatigue) congestion, miosis, (nasal ects tachycardia); compensatory hypotension, (postural eff eff mouth, slight (dry CV GIirritation); ects ects effCNS convulsions); GI (confusion, drowsiness, ects - Blood volume must be maintained before & after &after before maintained volumemust be Blood - Arrhythmia may &hypotension occur - continuously surgery during monitored &BPshouldbe forpre-op, ECG If used incombinationused tocontrol symptoms may Alpha-adrenergic also &beta-blockers blockers of ≥2L/day. forcrystals regularly urine Examine To tohave patients fl need avoid crystalluria uid intake marked or when tumor be manipulation will onlywhen other agents used Should are be ineff ective mouth, N/V,dry pain) abdominal GIeffconfusion); salivation, decreased (diarrhea, ects disorientation, disorders, psychiatric depression, effCNS anxiety, parkinsonism, trismus, (sedation, ects