1. Pheochromocytoma
Dr. Atallah Al-Ruhaily

2. Pheochromocytoma Catecholamine Physiology/Pathophysiology
Clinical Presentation
Epidemiology
Signs & Symptoms
Diagnosis
Biochemical
Localization
Management
Preoperative
Operative
Postoperative
Pregnancy

3. Catecholamine Producing Tumors
Neural Crest
Sympathoadrenal Progenitor Cell
(Neuroblasts)
Neuroblastoma
Chromaffin Cell
Sympathetic Ganglion Cell
Intra-adrenal Extra-adrenal
Pheochromocytoma
Ganglioneuroma

4. Catecholamine Producing Tumors
Pheochromocytoma
Paraganglioma (extra-adrenal pheo)
Originate in extra-adrenal sympathetic chain/chromaffin tissue
Ganglioneuroma
Behave like paraganglioma biochemically

5. Catecholamine Producing Tumors
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

6. Catecholamines Metabolites Tumor Secretion: Tyrosine L-Dopa DopamineTH
MAO, COMT
Tyrosine
L-Dopa
Dopamine
Homovanillic acid
(HVA)
DBH
COMT
Norepinephrine
Normetanephrine
PNMT
MAO
Epinephrine
COMT
Metaneprine
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
MAO
Vanillymandelic Acid
(VMA)
PNMT: Phenylethanolamine-N-Methyl Transferase
COMT : Catechol-O-Methyl Ttransferase
MAO: Mono-Amine Oxidase

7. 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

8. Pheochromocytoma Catecholamine Physiology/Pathophysiology
Clinical Presentation
Epidemiology
Signs & Symptoms
Diagnosis
Biochemical
Localization
Management
Preoperative
Operative
Postoperative
Pregnancy

9. Pheochromocytoma 0.01-0.1% of HTN population M = F
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 age < 20 or > 50 ?
Adrenal lesion found on imaging (ex. Incidentaloma)

10. Pheo: Signs & Symptoms The five P’s: The Classical Triad: Paroxysms
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

11. 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)

12. 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)

13. 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

14. Pheo: Signs (metabolic)
Hypercalcemia
Associated MEN2 HPT
PTHrP secretion by pheo
Mild glucose intolerance
Lipolysis
Weight-loss
Ketosis > VLDL synthesis (TG)

15. 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

16. 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)

17. Pheochromocytoma Catecholamine Physiology/Pathophysiology
Clinical Presentation
Epidemiology
Signs & Symptoms
Diagnosis
Biochemical
Localization
Management
Preoperative
Operative
Postoperative
Pregnancy

18. 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 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

19. 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

20. 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

21. 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

22. Plasma Metanephrines Not postural dependent: can draw normally
Secreted continuously by pheo
SEN 99% SPEC 89%
False Positive: acetaminophen

23. Biochemical Tests: Summary
SEN
SPEC
Ucatechols
83%
88%
Utotal metanephrines
76%
94%
Ucatechols+metaneph
90%
98%
UVMA
63%
Plasma catecholamines
85%
80%
Plasma metanephrines
99%
89%

24. 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

25. Localization: Imaging
CT abdomen
Adrenal pheo SEN %
Extra-adrenal pheo SEN 90%
MRI
> SEN than CT for extra-adrenal pheo

27. Localization: Imaging
CT abdomen
Adrenal pheo SEN %
Extra-adrenal pheo SEN 90%
MRI
> SEN than CT for extra-adrenal pheo
MIBG Scan
SEN 77-90% SPEC %

28. MIBG Scan 123I or 131I labelled metaiodobenzylguanidine
MIBG catecholamine precurosr taken up by the tumor
Inject MIBG, 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

30. Localization: Nuclear medicine
MIBG
111Indium-pentreotide
Some pheo have somatostatin receptors
PET
18F-fluorodeoxyglucose (FDG)
6-[18F]-fluorodopamine

32. Pheochromocytoma Catecholamine Physiology/Pathophysiology
Clinical Presentation
Epidemiology
Signs & Symptoms
Diagnosis
Biochemical
Localization
Management
Preoperative
Operative
Postoperative
Pregnancy

33. Pheo Management
Prior to 1951, reported mortality for excision of pheochromoyctoma %
HTN crisis, arrhythmia, MI, stroke
Hypotensive shock
Currently, mortality: %
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

34. Preop W/up CBC, lytes, creatinine, INR/PTT CXR EKG
Echo (r/o dilated CMY 2º catechols)

35. Preop Preperation Regimens
Combined  +  blockade
Phenoxybenzamine
Selective 1-blocker (ex. Prazosin)
Propanolol
Metyrosine
Calcium Channel Blocker (CCB)
Nicardipine

36. Preop:  +  blockade Start at least 10-14d preop Phenoxybenzamine
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 mg/d
Increase until BP cntrl and no more paroxysms
Maintenance mg/d (some need > 200 mg/d)
Salt load: NaCl 600 mg od-tid as tolerated

37. Preop:  +  blockade Phenoxybenzamine (cont’d) Selective 1-blockers
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)

38. 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

39. Preop:  +  blockade If BP still not cntrl despite  +  blockade
Add Prazosin to Phenoxybenzamine
Add CCB, ACE-I
Avoid diuretics as already ECFv contracted
Metyrosine

40. 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

41. Pheo: Rx of HTN Crisis IV phentolamine IV NTP IV esmolol
IV labetalol – combined  +  blocker

42. Preop: Metyrosine Synthetic inhibitor of Tyrosine Hydroxylase (TH)
L-Dopa
Dopamine
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
DBH
Norepinephrine
PNMT
Epinephrine

43. Preop: CCB CCB Nicardipine: most commonly used agent
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

44. 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!

45. O.R. Anesthetic choice: Laprascopic adrenalectomy if tumor < 8cm
Enflurane or isoflurane: don’t sensitized myocardium to catecholamines
Halothane: may sensitize heart  arrhythmia
Laprascopic adrenalectomy if tumor < 8cm

46. Postop Most cases can stop all BP meds postop
Postop hypotension: IV crystalloid
HTN free: 5 years 74% years 45%
24h urine collection 2 wk postop
Surveillance:
24h urine collections q1y for at least 10y
Lifelong f/up

47. 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

48. 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:
When fetus large enough: cesarian section followed by tumor resection