PHEOCHROMOCYTOMA-MANAGEMENT

Dr Karthik Balachandran

AGENDA

Introduction Diagnosis Management

Preop Intraop Postop and follow up

Special situations

INTRODUCTION

Catecholamine-secreting tumors that arise from chromaffin cells of the adrenal medulla

Term coined by Pick in 1912 To be distinguished from paraganglioma

Risk of malignancy Other neoplasms Genetic testing

CATECHOLAMINE SYNTHESIS

CATECHOLAMINE METABOLISM

CLINICAL SUSPICION

Pheochromocytoma should be suspected in patients who have one or more of the following:

• Hyperadrenergic spells (e.g., self-limited episodes of nonexertional palpitations, diaphoresis, headache, tremor, or pallor)• Resistant hypertension• A familial syndrome that predisposes to catecholamine-

secreting tumors (e.g., MEN2, NF1, VHL)

• A family history of pheochromocytoma• An incidentally discovered adrenal mass• Hypertension and diabetes• Pressor response during anesthesia, surgery, or

angiography• Onset of hypertension at a young age (<20 years)• Idiopathic dilated cardiomyopathy• A history of gastrointestinal stromal tumor or pulmonary

chondromas (Carney triad)

DIAGNOSTIC ALGORITHM

BIOCHEMICAL DIAGNOSIS

Measurement of metabolites better(intratumoral metabolism)

Plasma free metanephrines –screening test Absolute value important* Can be used in renal failure patients also(level-3 fold) Precautions for taking blood sample

*Sawka AM, Prebtani AP, Thabane L, et al. A systematic review of theliterature examining the diagnostic efficacy of measurement of fractionateplasma free metanephrines in the biochemical diagnosis ofpheochromocytoma. BMC Endocr Disord. 2004;4:2

PRECAUTIONS

Stop all interfering drugs Patients lying supine for at least 20 minutes before

sampling Sample through previously inserted iv line Avoid alcohol and nicotine x 12 hrs Preferably after an overnight fast Important for diagnostic cut offs(metanephrine, <0.3 nmol/L; normetanephrine,<0.66 nmol/L)

Lenders JW, Keiser HR, Goldstein DS, et al. Plasma metanephrines inthe diagnosis of pheochromocytoma. Ann Intern Med. 1995;123:101-109

URINE OR PLASMA?Test Sensitivity Specificity

24 hr urine fract metanephrines

98% 98%

Plasma frac metanephrines 96-100% 85-89%77%*

*older than 60 years

Plasma :•High negative predictive value•In children•In dopamine secreting tumors( plasma methoxy tyramine better than urinary dopamine/dihydroxyphenylalanine)

DIAGNOSTIC CLUE

Large Pheo: more metabolites (metabolized within tumor before release)• Small Pheo: more catecholamines• Sporadic Pheo: Norepi > Epi• Familial Pheo: Epi > Norepi• Epinephrine in MEN2 and norepinephrine in VHL(due to

expression of PNMT)

CLONIDINE SUPPRESSION TEST

Not in all cases-confirmatory To tackle false positives centrally acting α2- agonist that normally suppresses the

release of catecholamines from neurons but does not affect the catecholamine secretion from a pheochromocytoma

0.3 mg clonidine- measure catecholamines and metanephrines before and 3 hr after

Positive if Norepinephrine + epinephrine <500 pg/ml or >50% decrease

in norepinephrine Plasma normetanephrine 40% reduction

LOCALISATION

CT or MRI is the initial localisation test Sensitivity >95%; specificity >65% Imaging phenotype

CT enhancement,slow washout Variable size(average 4.5 cm) Bilaterality cystic and hemorrhagic changes high signal intensity on T2-weighted MRI

NEWER MODALITY

Chemical shift MRI Principle : hydroegen protons in water and lipid

resonate at different frequencies Pheo –low lipid In phase vs out of phase Benign adenomas lose signal in out of phase techniques

CHEMICAL SHIFT MRI

NUCLEAR IMAGING

Indications Negative abdominal imaging Pheo >10 cm Paragangliomas

123I-MIBG is superior to 131I-MIBG Inject MIBG, scan @ 24h, 48h, 72h Lugol’s 2 drops 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

NUCLEAR IMAGING

111Indium-pentreotide Some pheo have somatostatin receptors

PET 18F-fluorodeoxyglucose (FDG)-in advanced cases 6-[18F]-fluorodopamine- excellent sensitivity

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 WORKUP

CBC, electrolytes, creatinine, INR/PTT CXR EKG Echo (r/o DCM )

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 Drug of choice-western literature 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/DCM start low dose Propanolol most studied in pheo prep

Start 10 mg po bid increase to cntrl HR(60-80/m)

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

PREOP: METYROSINE

Synthetic inhibitor of Tyrosine Hydroxylase (TH) 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

PHEO: RX OF HTN CRISIS

IV phentolamine-1mg iv f/b 5mg bolus/infusions

IV NTP –not more than 3 mic/kg/min

Iv nicardipine -5 mg/hour

ANESTHESIA AND SURGERY

Α-and β-adrenergic blockers can be administered early in themorning on the day of the operation

Avoid fentanyl,ketamine,morphine,desflurane,halothane Preferred induction- propofol/etomidate Laparascopy for <8cm tumor

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

PERSISTENT HTN

Accidental ligation of a polar renal artery, resetting of baroreceptors

Hemodynamic changes Structural changes of the blood vessels Altered sensitivity of the vessels to pressor substances Functional or structural renal changes Coincident primary hypertension

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