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

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, glomus jugulare: Norepi Gangioneuroma: Norepi Malignant Pheo: Dopamine, HVA Neuroblastoma: Dopamine, HVA

Vanillymandelic Acid (VMA)

Adrenergic Receptors

Alpha-Adrenergic Receptors

1: vasoconstriction, intestinal relaxation, uterine contraction, pupillary dilation 2: presynaptic NE (clonidine), platelet aggregation, vasoconstriction, insulin secretion 1: HR/contractility, lipolysis, renin secretion 2: vasodilation, bronchodilation, glycogenolysis 3: lipolysis, brown fat thermogenesis

Beta-Adrenergic Receptors

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.

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 Ps:

Pressure (HTN) Pain (Headache) Perspiration Palpitation Pallor

90% 80% 71% 64% 42%

Paroxysms (the sixth P!)

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 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), 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) Caf-au-lait spots, neurofibroma, optic glioma Familial paraganglioma Familial pheo & islet cell tumor Other: Tuberous sclerosis, Sturge-Weber, ataxia-telangectgasia, Carneys Triad (Pheo, Gastric Leiomyoma, Pulm chondroma)

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.

24h Urine Collection

24h urine collection:

Creatinine, catecholamines, metanephrines, vanillymandelic acid (VMA), +/-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 (6.5 umol/d) 24h UVMA > 3-fold elevation
ULN 35 umol/d for most assays

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

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 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%

Suppression/Stimulation Testing

Clonidine suppression

May precipitate hypotensive shock! Unlike normals, pheo patients wont suppress their plasma norepi with clonidine May precipitate hypertensive crisis! Pheo patients, but not normals, will have a > 3x increase in plasma norepi with glucagon

Glucagon stimulation

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%

MIBG Scan
123I

or 131I labelled metaiodobenzylguanidine MIBG catecholamine precurosr taken up by the tumor Inject MIBG, scan @ 24h, 48h, 72h Lugols 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

MIBG 111Indium-pentreotide

Some pheo have somatostatin receptors

18F-fluorodeoxyglucose

PET

(FDG)

6-[18F]-fluorodopamine

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.

Pheo Management

Prior to 1951, reported mortality for excision of pheochromoyctoma 24 - 50 %

HTN crisis, arrhythmia, MI, stroke Hypotensive shock Preoperative preperation, -blockade? New anesthetic techniques?
Anesthetic agents Intraoperative monitoring: arterial line, EKG monitor, CVP line, Swan-Ganz

Currently, mortality: 0 - 2.7 %

Experienced & Coordinated team:

Endocrinologist, Anesthesiologist and Surgeon

Preop W/up

CBC, lytes, creatinine, INR/PTT CXR EKG Echo (r/o dilated CMY 2 catechols)

Preop Preperation Regimens

Combined + blockade

Phenoxybenzamine Selective 1-blocker (ex. Prazosin) Propanolol

Metyrosine Calcium Channel Blocker (CCB)

Nicardipine

No Randomized Clinical Trials to compare various regimens!

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 (contd)

Side-effect: orthostasis with dosage required to normalized seated BP, reflex tachycardia Drawback: periop hypotension/shock unlikely to respond to pressor agent. 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)

Selective 1-blockers

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 phentolamine IV NTP IV esmolol IV labetalol combined + blocker

Preop: Metyrosine
Tyrosine

TH

L-Dopa

Dopamine

Synthetic inhibitor of Tyrosine DBH Hydroxylase (TH) Norepinephrine Special pharm access, no DIN PNMT Start 250 mg qid max 1 gm qid Epinephrine Severe S/Es: 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

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

Preop: CCB

Cleveland Clinic:

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

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!

O.R.

Anesthetic choice:

Enflurane or isoflurane: dont 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 postop Surveillance:

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

Phenoxybenzamine + blocker prep When fetus large enough: cesarian section followed by tumor resection

3rd trimester: