PHEOCHROMOCYTOMA

FOCUS ON PRACTICAL POINT

ี Paisit Kosum, M.D.

Department of Medicine
Faculty of Medicine
Naresuan University

4th May 2017

OUTLINE
Introduction
Clinical presentation
Genetic and syndromic forms
Diagnostic investigation
Imaging studies
Perioperative management
Postoperative follow-up
PHEOCHROMOCYTOMA
Rare neuroendocrine tumor of adrenal medulla
Originating in chromaffin cells, or extra-adrenal chromaffin tissue
secretes excessive amounts of catecholamine
Catecholamine: epinephrine and norepinephrine
Hormones that regulate heart rate and blood pressure
Prevalence: 0.1 – 0.6% (Male: Female = 1:1)
10% associated with malignancy, 20% bilateral
PHEOCHROMOCYTOMA
CHARACTERISTIC
Size from 2 to 3600 g and are typically not encapsulated
Microscopically, composed of nests or cords of polyhedral cells
separated by fibrovascular stroma
Nuclear pleomorphism does not correlate with malignant behavior
Malignancy is diagnosis by clinically based on presence of extensive local
invasion or metastatic disease
Metastases must be distinguished from multifocal tumors occurring
elsewhere in areas of neural crest tissue
PHEOCHROMOCYTOMA: RULE OF 10
10% extra-adrenal (closer to 15%)
10% occur in children
10% familial (closer to 30%)
10% bilateral or multiple (more if familial)
10% recurrent (more if extra-adrenal)
10% malignant
10% discovered incidentally
 CATECHOLAMINE PRODUCING TUMOR
Neural Crest

Sympathoadrenal Progenitor Cell (Neuroblasts) Neuroblastoma

Chromaffin Cell Sympathetic Ganglion Cell

Intra-adrenal Extra-adrenal Ganglioneuroma

Pheochromocytoma
CATECHOLAMINE PRODUCING TUMOR
Pheochromocytoma
Paraganglioma (extra-adrenal pheochromocytoma)
Ganglioneuroma
Behave like paraganglioma biochemically
Neuroblastoma
Common malignancy in children, adrenal or sympathetic chain
Rapid growth & widespread metastasis
Some differentiate and spontaneously regress
HISTORY AND EMBRYOLOGY
Origin first described by Frankel in 1886
GA 5 weeks: first migration
Neuroblasts migrate from thoracic neural crest to form sympathetic chains and
preaortic ganglia (precursors of neuroblastomas and ganglioneuromas)
GA 7 weeks: second migration of cells (chromaffin cells) occurs to form
adrenal medulla to:
Sympathetic ganglia, vagus nerve, paraganglia of carotid arteries, arch of aorta,
abdominal aorta
Less commonly to wall of urinary bladder, prostate, behind liver, hepatic and renal
hila, and near rectum and gonads
ADRENAL GLANDS
NOMENCLATURE
Pheochromocytomas and paragangliomas arise from chromaffin cells
Usually develops in the center (medulla) of one or both adrenal glands
Paraganglioma is any extra-adrenal tumor of paraganglion system
Tumors in head, neck, and paravagal region are usually nonfunctioning
Tumors around aorta and sympathetic chain and visceral tumors, such as
bladder tumors, usually elaborate catecholamine
EXTRA ADRENAL SITE
Within sympathetic nerve chain along spinal cord
(orange spots)
Overlying distal aorta (main artery from heart)
(green spots)
Within ureter (collecting system from kidney
(yellow spot)
Within urinary bladder (blue spot)
50% are in adrenal glands (red spots on kidneys)
PARAGANGLIOMA
Paraganglioma were there is chromaffin tissue
Paraaortic sympathetic chain (organ of Zuckerkandl: origin of IMA), wall
of urinary bladder, along sympathetic chain in neck or mediastinum
Paraganglioma in mediastinum, abdomen, pelvis usually arise from
sympathetic chromaffin tissue: secrete catecholamine
Paraganglioma in head and neck region usually arise from
parasympathetic tissue: typically do not secrete catecholamine
TUMOR LOCATION
50% arise in adrenal medulla
Most extra-adrenal pheochromocytomas (functional paragangliomas)
occur in abdomen along great vessels
Most commonly in upper periaortic region from diaphragm to lower
poles of kidneys
Extra-adrenal tumors may also occur at base of skull, in chest (including
heart and pericardium), or paratesticularly
BIOSYNTHESIS OF CATECHOLAMINE
TUMOR SECRETION
Large pheochromocytoma: more metabolites (within tumor before release)
Small pheochromocytoma: more catecholamine
Sporadic pheochromocytoma : norepinephrine > epinephrine
Familial pheochromocytoma : epinephrine > norepinephrine
Paraganglioma: norepinephrine
Gangioneuroma: norepinephrine
Malignant pheochromocytoma : Dopamine, HVA
Neuroblastoma: Dopamine, HVA
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
CLINICAL PRESENTATION
Occur with equal frequency in men and women
Frequency in age group of 30-50
Rare in children (multifocal and hereditary syndrome)
Symptom cause from excess concentration of circulating catecholamine
Associated hypertension may be sustained or paroxysmal
Episodic release of catecholamine
Chronic volume depletion and impaired sympathetic reflexes
CLINICAL PRESENTATION
Orthostatic hypotension occur in case of epinephrine or dopamine
predominant tumor
Episodic symptom may occur in spell or paroxysmal
Forceful heartbeat
Pallor
Tremor
Headache
Diaphoresis
CLINICAL PRESENTATION: SPELL
Spell may start with sensation of “rush” in chest and sense of shortness
of breath, followed by forceful heartbeat and throbbing headache
Peripheral vasoconstriction: associated with spell results in cool or cold
hands and feet and facial pallor
Increase sense of body heat and sweating are common symptoms that
occur toward end of spell
Spell may be either spontaneous or precipitated
PRECIPITATING FACTOR OF SPELL
Postural change
Anxiety
Medication (beta blockers, metoclopramide, anesthetic agents)
Exercise
Maneuvers that increase intra-abdominal pressure (change in position,
lifting, defecation, colonoscopy, pregnancy, trauma)
CLINICAL PRESENTATION: SPELL
Spell in patient population are highly variable
Spell tend to be stereotypical for each patient
May occur multiple times daily or infrequently as once monthly
Typical duration: 15-20 minutes (may be shorter or last severe hours)
However, most patients with spells do not have pheochromocytoma
SIGNS AND SYMPTOMS
Spell-related signs and symptoms
Anxiety and fear of Hypertension
impending death Nausea and vomiting
Diaphoresis Pallor
Dyspnea Palpitation (forceful heartbeat)
Epigastric and chest pain Tremor
Headache
SIGNS AND SYMPTOMS
Chronic signs and symptom
Cold hand feet Fatigue
CHF: cardiomyopathy Fever
Constipation General increase in sweating
Diaphoresis Grade II-IV hypertensive retinopathy
Dyspnea Headache
Ectopic hormone secretion Hyperglycemia
Epigastric and chest pain Hypertension
SIGNS AND SYMPTOMS
Chronic signs and symptom Not typical of pheochromocytoma
Nausea and vomiting Flushing
Orthostatic hypotension
Painless hematuria
Pallor
Palpitation (forceful heartbeat)
Tremor
Weight loss
DDX OF PHEOCROMOCYTOMA-TYPE SPELL
Endocrine causes
Carbohydrate intolerance
Hyperadrenergic spells
Hypoglycemia
Pancreatic tumor (e.g. insulinoma)
Pheochromocytoma
Primary hypogonadism (menopause)
Thyrotoxicosis
Cardiovascular causes
Angina
Labile essential hypertension
Orthostatic hypotension
Paroxysmal cardiac arrhythmia
Pulmonary edema
Renovascular disease
Syncope (e.g. vasovagal reaction)
DDX OF PHEOCROMOCYTOMA-TYPE SPELL
Psychological causes
Factitious (e.g. drug,Valsalva
maneuver)
Hyperventilation
Severe anxiety and panic
disorders
Somatization disorder
Neurologic causes
Autonomic neuropathy
Cerebrovascular insufficiency
Diencephalic epilepsy (autonomic seizures)
Migraine headache
Postural orthostatic tachycardia syndrome
Stroke
DDX OF PHEOCROMOCYTOMA-TYPE SPELL

Pharmacologic causes
Chlorpropamide-alcohol flush
Combination of monoamine oxidase inhibitor and decongestant
Illegal drug ingestion (cocaine, phencyclidine, lysergic acid diethylamide)
Sympathomimetic drug ingestion
Vancomycin (red man syndrome)
Withdrawal of adrenergic-inhibitor
DDX OF PHEOCROMOCYTOMA-TYPE SPELL

Other causes
Carcinoid syndrome
Mast cell disease
Recurrent idiopathic anaphylaxis
Unexplained flushing spells
ADDITIONAL CLINICAL SIGNS
Hypertensive retinopathy Constipation
Orthostatic hypotension Raynaud phenomenon
Angina Livedo reticularis
Nausea Erythrocytosis
Hyperglycemia Mass effect from tumor
Diabetes mellitus Painless hematuria
Hypercalcemia Cardiomyopathy, CHF, MI
CO-SECRETED HORMONE
ACTH (Cushing syndrome)
Parathyroid hormone-related peptide (hypercalcemia)
Vasopressin (SIADH)
Vasoactive intestinal peptide (watery diarrhea)
Growth hormone-releasing hormone (acromegaly)
FINDING ASSOCIATED GENETIC SYNDROMES

Retinal angiomas
Iris hamartomas
Marfanoid body habitus
Café au lait spots
Axillary freckling
Subcutaneous neurofibromas
Mucosal neuroma on eyelids and tongue
GENETIC AND SYNDROMIC FORMS
Since 1990 found susceptibility gene at least 14 genes
NF1, RET, VHL, SDHD, SDHC, SDHB, EGLN1/PHD2, K1F1β,
SDH5/SDHAF2, IDH1,TMEM127, SDHA, MAX, HIF2
1 in 3 have germline mutation
Found in younger age
Found since initial stage of disease (biochemical surveillance or genetic
testing)
MULTIPLE ENDOCRINE NEOPLASIA TYPE 2A
Multiple Endocrine neoplasia type 2A (MEN2A): Sipple syndrome
Autosomal dominant disorder
MEN2A characterized by
Medullary thyroid cancer (MTC) in all patients
Adrenergic (epinephrine and metanephrines are predominant)
pheochromocytoma in 50% (usually bilateral and asynchronous)
Primary hyperparathyroidism in 20%
Cutaneous lichen amyloidosis 5%, very rarely Hirschsprung disease
MULTIPLE ENDOCRINE NEOPLASIA TYPE 2A
Prevalence: 1 in 200,000 live births
MTC usually detected before pheochromocytoma is diagnosed
Numerous activating mutation: RET (REarranged during Transfection):
proto-oncogene
Located on chromosome 10q11.2
Distinguish constipation/obstipation due to Hirschsprung disease in
MeD2A from due to ganglioneuromatosis of MEN2B
MULTIPLE ENDOCRINE NEOPLASIA TYPE 2B
MEN2B: Gorlin syndrome, approximately 5% of all MEN2 cases
Autosomal dominant disorder
MEN2B characterized by
Medullary thyroid cancer (MTC) in all patients
Adrenergic (epinephrine and metanephrines are predominant)
pheochromocytoma in 50%
Mucocutaneous neuromas (tongue, lips, eyelids) in most patients
Skeletal deformities (e.g. kyphoscoliosis, lordosis)
MULTIPLE ENDOCRINE NEOPLASIA TYPE 2B
MEN2B characterized by (cont.)
Joint laxity
Myelinated corneal nerves
Intestinal ganglioneuromas
Marfanoid habitus
Associated by mutations in RET
> 95% of MEN2A, > 98% of MEN2B have identifiable mutation in RET
prot-ooncogene
VON HIPPEL-LINDAU DISEASE
VHL syndrome is autosomal dominant disorder
Manifest with variety of benign and malignant neoplasm
Noradrenergic (norepinephrine and normetanephrine are predominant)
pheochromocytoma or
Paraganglioma (mediastinal, abdominal, pelvic)
Hemangiobalstoma (cerebellum, spinal cord, brain stem)
Retinal angioma
Clear cell renal cell carcinoma
VON HIPPEL-LINDAU DISEASE
Manifest with variety of benign and malignant neoplasm (cont.)
Pancreatic neuroendocrine tumors
Endolymphatic sac tumors of middle ear
Serous cystadenomas of pancreas
Papillary cystadenomas of epididymis and broad ligament
100% found by age 65 years (average 20-29 years)
Prevalence: 1:35,000 – 1:90,000
VON HIPPEL-LINDAU DISEASE
VHL tumor suppressor gene
Located on chromosome 3p25-26
VHL lead to inappropriate activation of
hypoxic response (promoting glycolysis,
angiogenesis, proliferation)
• Type 1: no pheochromocytoma
• Type 2: have pheochromocytoma
- Type 2A: no RCC
- Type 2B: have RCC too
- Type 2C: have only pheochromocytoma
NEUROFIBROMATOSIS TYPE 1
NF1 previously known as von Recklinghausen disease
One of the most common genetic syndrome
Prevalence: 1 in 2,000 – 1 in 1,5000
Autosomal dominant disorder
Associated with NF1 tumor suppressor gene
Located on chromosome 17q11.2
NEUROFIBROMATOSIS TYPE 1
Characterized by
Neurofibromas, multiple café au lait spots
Axillary and inguinal freckling
Iris hamartomas (Lisch nodule)
Bony abnormalities
Central nervous system glioma
Pheochromocytoma and paraganglioma
Macrocephaly, cognitive deficits
NEUROFIBROMATOSIS TYPE 1
2% of patients with NF1 develop catecholamine-secreting tumor
If have catecholamine-secreting tumor
Usually solitary and benign adrenal pheochromocytoma
Occasionally bilateral adrenal pheochromocytoma
Rarely abdominal periadrenal paraganglioma
Frequently, adrenal pheochromocytoma is detected as incidental adrenal
mass on imaging
FAMILIAL PARAGANGLIOMA
Age group 30-35 years
Autosomal dominant disorder
Most common found at skull base and neck
Other locations: mediastinum, abdomen, pelvis, urinary bladder
Producing catecholamine depend on location
Skull base and neck: produce hormone 5%
Abdomen: produce hormone 50%
FAMILIAL PARAGANGLIOMA
Mutation of succinate dehydrogenase (SDH) subunit: consist of
mitochondrial complex II (tumor suppressor gene) for electron
transport chain and tricarboxylic acid (TCA) cycle
SDHB, SDHC, SDHD, SDHA, SDHAF2
SDHD or paraganglioma syndrome type 1: inactivating germline mutation
on chromosome 11q 23
SDHC or paraganglioma syndrome type 3: missence mutation on
chromosome 1q21
FAMILIAL PARAGANGLIOMA
SDH complex assembly factor 2 (SDHAF2) or paraganglioma syndrome
type 2: loss of function mutation on chromosome 11q13.1
SDHD, SDHC, SDHAF2: found parasympathetic paraganglioma at skull
base and neck
SDHB or paraganglioma syndrome type 4: inactivating mutation of tumor
suppressor gene on chromosome 1p35-36
Associated with paraganglioma at abdomen, pelvis, mediastinum
Found adrenal pheochromocytoma 40%
FAMILIAL PARAGANGLIOMA
SDHB mutation
Risk of malignant paraganglioma
Risk of renal cell carcinoma
Risk of papillary thyroid carcinoma
NEUROCUTANEOUS SYNDROME
Ataxia-telangiectasia
Tuberous sclerosis
Sturge-Weber syndrome
Carney triad
Gastrointestinal stromal tumor
Pulmonary chondroma
Catecholamine-secreting paraganglioma
GENETIC TESTING
Should be consider if has one or more of the following
Paraganglioma
Bilateral adrenal pheochromocytoma
Unilateral adrenal pheochromocytoma and family history of pheochromocytoma
or paraganglioma
Unilateral adrenal pheochromocytoma with onset at younger age (< 45 years)
Other clinical findings suggestive of one of the previously discussed syndromic
disorders
CASE DETECTIONS
Should be suspected in patients who have one or more of the following
Hyperadrenergic spell
Resistant hypertension
Familial syndrome that predisposes to catecholamine-secreting tumors
Family history of pheochromocytoma
Incidentally discovered adrenal mass with imaging characteristics consistent with
pheochromocytoma
Pressor response during anesthesia, surgery, or angiography
Onset of hypertension at young age (< 20 years)
Idiopathic dilated cardiomyopathy
DIAGNOSTIC INVESTIGATION
Levels of fractionated catecholamine and metanephrine may be elevated
in severe clinical scenarios
Withdrawal from medications or drug (e.g. clonidine, alcohol)
Any acute illness (e.g. subarachnoid hemorrhage, migraine headache, preeclampsia)
Administration of many drugs and medications (e.g. TCA, levodopa, buspirone,
antipsychotic agents, cocaine, phencyclidine, amphetamines, ephedrine,
pseudoephedrine, phenylpropanolamine, isoproterenol)
AVAILABLE TEST AND TEST PERFORMANCE
Catecholamine metabolism: enzymatic pathway
Catechol-O-methyltransferase (COMT): epinephrine --> metanephrine
Meta-O-methylation: norepinephrine --> normetanephrine
Metanephrine and normetanephrine oxidized by monoamine oxidase
(MAO) --> vanillylmandelic acid (VMA) metabolites
Fractionated catecholamine: dopamine, norepinephrine, epinephrine
Fractionated metanerphine: metanephrine, normetanephrine
AVAILABLE TEST AND TEST PERFORMANCE
Techniques
High-performance liquid chromatography with electrochemical detection
(HPLC-ECD)
Liquid chromatography with tandem mass spectrometry (LC-MS/MS)
2 techniques can solve false positive and imprecision problems by
immunoassay
False positive results caused by α-methyldopa, labetalol, sotalol, imaging
contrast agents
AVAILABLE TEST AND TEST PERFORMANCE
Urine fractionated metanerphrine is more sensitivity and accuracy, less
false negative than urine catecholamine or urine VMA
Plasma free metaneprhine is the most high sensitivity
(sensitivity 96-100%, specificity 80-98%)
Urine fractionated metaneprhine (sensitivity 85-97%, specificity 68-95%)
Urine VMA is high specificity but the lowest sensitivity (not diagnosis)
Endocrine Society Committee recommend
Plasma free metanephrine or 24-hour urine fractionate metanephrine
SENSITIVITY AND SPECIFICITY OF TEST
SENSITIVITY AND SPECIFICITY OF TEST
Sensitivity (%) Specificity (%)
Technique
Hereditary Sporadic Hereditary Sporadic
Plasma
Free metanephrine 97 99 96 82
Catecholamine 69 92 89 72
Urine
Fractionated metanephrine 96 97 82 45
Catecholamine 79 91 96 75
Total metanephrine 60 88 97 89
Vanillylmandelic acid (VMA) 46 77 99 86
SOURCE OF FALSE POSITIVE TESTS RESULTS
Exercise
Position (upright)
Diet (high tyramine)
Stress
Hypoglycemia
Drugs
 NATURE OF BIOCHEMICAL INTERFERENCE
Analytical interference
Coffee HPLC assays: plasma catecholamine
Labetalol Spectrophotometric and fluorometric assay: urine
metanephrine, catecholamine
Sympathomimetics (amphetamine, ephridine) Spectrophotometric and fluorometric assay: plasma and
urine metanephrine, catecholamine
Methyl-dopa HPLC assays: catecholamine
Sotolol HPLC assays: plasma catecholamine
Paracetamol HPLC assays: plasma free metanephrine
L-dopa HPLC assays: catecholamine and metabolites
Vanilla, Banana, Coffee, Chocolate, Citrus fruit Column test: urine VMA
 NATURE OF BIOCHEMICAL INTERFERENCE
Pharmacodynamic and pharmacokinetic interferences
Tricyclic antidepressants Block NE reuptake, increase NE Falsely positive NE, NMN, VMA
Labetalol, Phentolamine, Inhibit receptors and increase plasma Falsely positive E, NE
Phenoxybenzamine, catecholamine
Theophylline, diuretics
Methyl dopa, L-dopa, Metabolized by enzyme that convert Falsely positive
dopaminergic drugs catecholamine
Antiparkinson, Bromocriptine, Inhibition of central sympathetic out flow Falsely negative
Antipsychotic, Clonidine
Contrast media, reserpine Inhibit tyrosine hydroxylase Falsely negative urine
(Methylglucamine) metanephrine
RECOMMEND FOR BIOCHEMICAL TESTING
No major physical stress
Avoid analytical methods interference (Vanilla, Banana, Coffee, Chocolate)
Hold following medications for 2 weeks
Drugs that effect sympathomimetic pathway for 1-2 week: TCAs, MAOI,
levodopa, methyldopa, labetalol, clonidine (withdrawal), sympathomimetics,
Phenoxybenzamine
Toxic: alcohol, cocaine, amphetamine, opiate
Anti-HT agents that can be prescribed before test
α1 adrenergic blockade + β blocker, CCB, Vasodilators, ACEI, ARB
RECOMMEND FOR BIOCHEMICAL TESTING
Situation Recommendation
Patient Preparation • Avoid sympathomimetic agents (including ephedrine,
amphetamine, nicotine)
• Avoid interfering medications
• Overnight fast, no caffeinated or decaffeinated beverages
Conditions for blood • Supine condition, after 30 min rest
sampling of metanephrine • Collection in heparinized tubes on ice
• Storage in freezer at -20oC if measured within 3 months
Conditions for urine • Collection in container without additives or eventually only
sampling of metanephrine sodium bisulphate
• Storage of urine container in cold place
• Acidify urine in laboratory to pH 4 before storing
SOURCE OF FALSE NEGATIVE TESTS RESULT
Causes
Tumor size < 1 cm (asymptomatic)
Dopamine producing tumors
Microscopic recurrent disease
SDHx mutation
Need further investigations
3-methoxytyramine, plasma chromogranin A
Imaging studies
INTERPRETATION OF TEST RESULTS
Plasma free metanephrine and urine fractionated metanephrine: high
sensitivity test
False positive 19-21%
Diagnosis: increase metanephrine or normetanephrine > 3X
If metanephrine or normetanephrine < 3X
Clonidine suppression test: specificity 100%, sensitivity 97%
Chromogranin A: positive 80% in pheochromocytoma and paraganglioma
FOLLOW UP
Endocrine Society Committee recommend
F/U in patients with positive biochemical test
Interval and imaging depend on individual
IMAGING STUDIES
Imaging studies perform after biochemical tests except paragangliomas
at skull base/neck and paraganglioma (SDHx mutations)
Imaging of choice: CT scan with contrast (abdomen and pelvis)
Sensitivity 88-100%, detect tumor size at least 5 mm
Findings: homogenous or heterogenous, necrotic, calcification, solid or cystic
87-100% of tumor attenuation > 10 Hounsfield units in unenhanced CT and
washout contrast agent > 60% in 15-min delayed scanning
Nonionic contrast: safe in patient not receive adrenergic receptor blocker
CT SCAN
CT SCAN
Lipid-rich nature of cortical adenomas helpful in distinguishing benign
neoplasm from pheochromocytoma
Adipose tissue: typical -20 to -50 HU
Kidney: typical 20 to 50 HU
If adrenal mass < 0 HU on unenhanced CT favor benign adenoma
Adrenal adenoma show much earlier washout of contrast enhancement
than do nonadenoma (51% at 5 min, 70% at 15 min compared with 8%
and 20% respectively for nonadenoma)
CT SCAN
MRI
Several different MRI techniques used to characterize adrenal masses
Conventional spin-echo MRI is the first and still most frequently used
On gadolinium-diethylenetriaminepenta-acetic acid (DPTA)-enhanced
MRI, pheochromocytoma and malignant lesion show rapid and marked
enhancement and slower washout pattern
Adenoma: mild enhancement and rapid washout of contrast agent (similar
findings as CT)
Chemical shift MRI is form of lipid-sensitive imaging
MRI
Chemical shift MRI based on principle that
hydrogen protons in water and lipid molecules
resonate at different frequencies
Benign cortical adenoma contain approximately
equal amounts of lipid and water, whereas lipid
content of pheochromocytoma is usually low
MRI: good for extra-adrenal, residual, recurrent
or metastatic tumor (sensitivity 90-95% whereas
CT sensitivity 57%)
MIBG SCINTIGRAPHY
123I-metaiodobenzylguanidine (MIBG) scintigraphy
If abdominal imaging negative: 123I-MIBG is indicated
Sensitivity 80%, Specificity 99%
Indication
Suspected metastatic PPGLs (e.g. primary tumor > 10 cm)
Extra-adrenal multifocal PPGLs (except skull base and neck)
Recurrent PPGLs
MIBG SCINTIGRAPHY
123I-MIBG is superior to 131I-MIBG
50% of normal adrenal gland can update 123I-MIBG
Pheochromocytoma: sensitivity 85-88%, specificity 70-100%
Paraganglioma: sensitivity 56-75%, specificity 80-100%
Metastatic PPGLs: sensitivity 56-83%
Recurrent PPGLs: sensitivity 75%
Many drugs may interfere MIBG uptake
DRUG INTERFERE MIBG UPTAKE
TREATMENT
Treatment of choice is complete surgical resection
Surgical survival rate 98-100%, highly depend on skill of endocrinologist,
endocrine surgeon, anesthesiologist team
Most common adverse event after surgery is sustained hypertension
Preoperative pharmacologic preparation: crucial for successful treatment
Most catecholamine-secreting tumor are benign and can totally excised
Tumor excision usually cures hypertension
PREOPERATIVE MANAGEMENT
Preoperative pharmacologic preparation is indicated for all patients with
catecholamine-secreting tumor (include asymptomatic & normotensive)
No RCT compared different approaches
Combined α and β-adrenergic blockage is one approach to control BP
and prevent intraoperative hypertensive crisis
α-adrenergic blockage should be started 7-10 days preoperatively to
normalize BP and expand contracted blood volume
Longer duration: recent MI, cardiomyopathy, vasculitis
PREOPERATIVE MANAGEMENT
BP should monitored with seated and standing position twice daily
Target BP is low-normal BP for age
BP < 120/80 mmHg in seated position
SBP > 90 mmHg (standing)
Second or third day of α-adrenergic blockage: encouraged start diet high
sodium content (≥ 5,000 mg/day)
Because of catecholamine-induced volume contraction
Orthostasis associated with α-adrenergic blockade
PREOPERATIVE MANAGEMENT
Caution in patient with CHF and CKD
After adequate α-adrenergic blockage, beta-adrenergic blocker is
initiated, typically 2-3 days preoperatively
ALPHA-ADRENERGIC BLOCKADE
Phenoxybenzamine is preferred drug for preoperative preparation to
control BP and arrhythmia
Irreversible, long-acting, nonspecific α-adrenergic blockade
Initial dose 10 mg once or twice daily
Increased by 10-20 mg in divided dose every 2-3 days
Final dose 20-100 mg/day
ADR: orthostasis, nasal congestion, retrograde ejaculation, marked fatigue
More favorable S/E: selective α1-adrenergic blockade
BETA-ADRENERGIC BLOCKADE
Should administered only after α-adrenergic blockade is effective
Because beta blocker alone may be severe hypertension or
cardiopulmonary decompensation
Result of unopposed α-adrenergic stimulation
Caution in patient with asthma or CHF
Initiation of beta blocker resulting in acute pulmonary edema (chronic
catecholamine excess --> cardiomyopathy)
Start with propranolol 10 mg q 6 hours (Goal HR 60-80 bpm)
CALCIUM CHANNEL BLOCKER
CCB block norepinephrine-mediated calcium transport into vascular
smooth muscle
Nicardipine is the most commonly used CCB in this setting
Starting dose 30 mg twice daily of sustained-release preparation
Use of CCB for perioperative management dose not prevent all
hemodynamic changes, but associated with low morbidity and mortality
 PRE-SURGICAL MEDICAL PREPARATION
Drug Starting time Start Dose Final Dose
Preparation 1
Phenoxybenzamine 10-14 day before surgery 10 mg bid 1 mg/kg/day
Doxazosin 10-14 day before surgery 2 mg/day 32 mg/day
Preparation 2
Nifedipine As add-on to preparation 1 when needs 30 mg/day 60 mg/day
Amlodipine As add-on to preparation 1 when needs 5 mg/day 10 mg/day
Preparation 3
Propranolol After at least 3-4 day of preparation 1 25 mg tid 40 mg tid
Atenolol After at least 3-4 day of preparation 1 25 mg/day 50 mg/day
ACUTE HYPERTENSIVE CRISIS
Occur before or during operation
Should treated with intravenously administered sodium nitroprusside,
phentolamine, or nicardipine
Sodium nitroprusside is ideal vasodilator of intraoperative management
of hypertensive episodes (rapid onset and short duration)
Dose 0.5-5.0 mcg/kg/min, adjust every few minutes
Keep steady-state thiocyanate concentration < 1 mmol/L
ACUTE HYPERTENSIVE CRISIS
Drug Preparation Dose Clinical Aspects
Nitroprusside 50 mg in 250 cc 0.5-5 Do not use for > 24
(Direct arterial vasodilator) of 5%D/W mcg/kg/min hour at high dose (> 5
Onset 30 sec, peak 2 min IV drip mcg/kg/min) cause
hypotension, tachycardia
Nicardipine 25 mg in 250 cc Loading 1-2.5 Tachycardia, may prevent
(Calcium channel blocker) of 5%D/W mg over 1-5 catecholamine induced
min then 5-15 coronary spasm
mg/hr IV drip
Magnesium sulfate 40 g in 500 cc Loading: 1-2 g Muscle weakness and
(Vasodilator) of Ringer’s IV and then hypermagnesemia
solution 1-3 g/hr
ANESTHESIA AND SURGERY
Last oral doses of alpha and beta adrenergic blocker can be administered
early in morning on day of operation
Avoid fentanyl, ketamine, morphine
Can stimulate catecholamine release from pheochromocytoma
Avoid atropine because of tachycardia
Anesthesia may be induce with propofol, etomidate, barbiturates in
combination with synthetic opioids
Avoid halothane and desflurane
ANESTHESIA AND SURGERY
Continuous measurement of intra-arterial pressure and heart rhythm
If patient with CHF or decreased cardiac reserve, should be PCWP
monitoring
Adrenal pheochromocytoma: laparoscopic approach should consider
(if mass size < 8 cm)
Avoid tumor capsule rupture
Transform benign pheochromocytoma to incurable one with diffuse
peritoneal disease
ANESTHESIA AND SURGERY
Paraganglioma: open resection should be considered
Hypotension may occur during and after surgical resection of
pheochromocytoma
Treat by fluids and colloids
Occur less frequency in adequate preoperative alpha adrenergic blockade
and volume expansion
Beware adrenocortical insufficiency
Hypoglycemia occur in immediate postoperative period
ANESTHESIA AND SURGERY
Blood glucose level should monitored
Fluid given intravenous should contain 5% dextrose
BP usually normal by time of hospital discharge
Long-standing, persistent hypertension due to
Resection-related renal injury Structural change of blood vessel
Resetting of baroreceptors Functional or structural renal change
Hemodynamic change Coincident primary hypertension
POSTOPERATIVE FOLLOW UP
1-2 weeks after surgery, measure 24-hour urinary fractionated
catecholamine and metanephrine
If level normal: complete resection
If level increase: residual tumor (second primary or occult metastasis)
If bilateral adrenalectomy: lifelong glucocorticoid and mineralocorticoid
replacement therapy
Risk for recurrent for benign PPGLs is 15% on long-term F/U
POSTOPERATIVE FOLLOW UP
24-hour urinary fractionated catecholamine and metanephrine or plasma
fractionated metaneprhine should checked annually
Recurrence rate highest of familial disease, large tumor size (> 5 cm), or
paraganglioma
Follow up CT or MRI is not need unless elevated urinary or plasma
fractionated metaneprhine
MALIGNANT PHEOCHROMOCYTOMA AND
PARAGANGLIOMA
Malignancy rare in patients with MEN2 or VHL syndrome
Common in familial paraganglioma by mutation in SDHB
5-year survival of malignant pheochromocytoma: < 50%
Prognosis is variable
50% of patients have indolent form (50% rapid progressive)
Life expectancy > 20 years
Death within 1-3 years after diagnosis
MALIGNANT PHEOCHROMOCYTOMA AND
PARAGANGLIOMA
Metastasis site: local tissue invasion, liver, bone, lung, omentum, LN
Metastatic lesion should be resected if possible
Treatment
Surgery
Radiotherapy
Cryotherapy
Chemothearpy
PHEOCHROMOCYTOMA AND PREGNANCY
Cause death of both fetus and mother
Biochemical diagnosis is same as nonpregnancy
MRI (without gadolinium enhancement) if preferred imaging
Contraindication: 123I-MIBG
Surgical resection should be consider in 1st or 2nd trimester
If 3rd trimester to performed C/S and surgical resection at same time
(avoid spontaneous labor)
TAKE HOME MESSAGE
Pheochromocytoma is rare neuroendocrine tumor of adrenal medulla
Important to suspect, confirm, localize and resect tumor because
Associated hypertension is curation with surgical removal
Risk of lethal paroxysm exists
At least 10% of tumor are malignant
40% of these tumor are familial (germline mutation)
PPGLs must be confirmed biochemically testing, then localized with CT
Preoperative preparation is indicated for all patient with PPGLs
PHEOCHROMOCYTOMA
FOCUS ON PRACTICAL POINT

The End
Thank you
for your attention
4th May 2017