Pheochromocytoma Dr. Atallah Al-Ruhaily. Pheochromocytoma 1. Catecholamine...

Pheochromocytoma

Dr. Atallah Al-Ruhaily

Pheochromocytoma

1. Catecholamine Physiology/Pathophysiology2. Clinical Presentation

1. Epidemiology2. Signs & Symptoms

3. Diagnosis1. Biochemical2. Localization

4. Management1. Preoperative2. Operative3. Postoperative4. Pregnancy

Catecholamine Producing Tumors

Neural Crest

Sympathoadrenal Progenitor Cell(Neuroblasts)

Chromaffin Cell Sympathetic Ganglion Cell

Intra-adrenal Extra-adrenalPheochromocytoma

Ganglioneuroma

Neuroblastoma

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)

Cheodectoma Carotid body, behave like paraganglioma biochemically

Glomus jugulare tumor Intracranial branch of CN IX and X Behave like paragangliomoa biochemically


Tyrosine L-Dopa Dopamine

Norepinephrine

Epinephrine

Catecholamines

Normetanephrine

Metaneprine

PNMT

DBH

COMT

COMT

Metabolites

Homovanillic acid(HVA)

MAO, COMT

Vanillymandelic Acid(VMA)

MAO

MAOTumor 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

TH

•PNMT: Phenylethanolamine-N-Methyl Transferase•COMT : Catechol-O-Methyl Ttransferase•MAO: Mono-Amine Oxidase

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

Pheochromocytoma





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)

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

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)

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, 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

Pheo: Signs (metabolic)

Hypercalcemia Associated MEN2 HPT PTHrP secretion by pheo

Mild glucose intoleranceLipolysis

Weight-loss Ketosis > VLDL synthesis (TG)

Pheo: ‘Rule of 10’

10% extra-adrenal (closer to 15%)10% occur in children10% familial (closer to 20%)10% bilateral or multiple (more if familial)10% recur (more if extra-adrenal)10% malignant10% discovered incidentally

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)

Pheochromocytoma





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

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

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

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

Plasma Metanephrines

Not postural dependent: can draw normallySecreted continuously by pheoSEN 99% SPEC 89%False Positive: acetaminophen

Biochemical Tests: SummarySEN SPEC

Ucatechols 83% 88%

Utotal metanephrines 76% 94%

Ucatechols+metaneph 90% 98%

UVMA 63% 94%

Plasma catecholamines 85% 80%

Plasma metanephrines 99% 89%

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

Localization: Imaging

CT abdomen Adrenal pheo SEN 93-100% Extra-adrenal pheo SEN 90%

MRI > SEN than CT for extra-adrenal pheo

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%

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

Localization: Nuclear medicine

MIBG111Indium-pentreotide

Some pheo have somatostatin receptors

PET 18F-fluorodeoxyglucose (FDG) 6-[18F]-fluorodopamine

Pheochromocytoma





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

Preop W/up

CBC, lytes, creatinine, INR/PTTCXREKGEcho (r/o dilated CMY 2º catechols)

Preop Preperation Regimens

Combined + blockade Phenoxybenzamine Selective 1-blocker (ex. Prazosin) Propanolol

Metyrosine Calcium Channel Blocker (CCB)

Nicardipine

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.

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)

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

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

Pheo: Rx of HTN Crisis

IV phentolamineIV NTPIV esmololIV labetalol – combined + blocker

Preop: Metyrosine

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

Tyrosine L-Dopa Dopamine

Norepinephrine

Epinephrine

PNMT

DBH

TH

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 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

O.R.Admit night before for overnight IV salineArterial line, EKG monitor, CVP lineKnown CHF: consider Swan-GanzRegardless 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!

O.R.

Anesthetic choice: Enflurane or isoflurane: don’t sensitized

myocardium to catecholamines Halothane: may sensitize heart arrhythmia

Laprascopic adrenalectomy if tumor < 8cm

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 postopSurveillance:

24h urine collections q1y for at least 10y Lifelong f/up

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

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

Pheochromocytoma Dr. Atallah Al-Ruhaily. Pheochromocytoma 1. Catecholamine...

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