Pheochromocytoma management

Presentation detailing the management of Pheochromocytoma

1. Pheochromocytoma -Management Dr Karthik Balachandran

2. Agenda Introduction Diagnosis Management Preop Intraop Postop and follow up Special situations

3. 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

4. Catecholamine synthesis

5. Catecholamine metabolism

6. 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)

7. • 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)

8. Diagnostic algorithm

9. 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 the literature examining the diagnostic efficacy of measurement of fractionate plasma free metanephrines in the biochemical diagnosis of pheochromocytoma . BMC Endocr Disord . 2004;4:2

10. 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 in the diagnosis of pheochromocytoma . Ann Intern Med. 1995;123: 101-109

11. 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 )

12. 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)

13. 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

14. 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

15. 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

16. 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

17. Chemical shift MRI

18. Nuclear imaging Indications Negative abdominal imaging Pheo >10 cm Paragangliomas 123 I-MIBG is superior to 131 I-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

19. Nuclear imaging

20. 111 Indium-pentreotide Some pheo have somatostatin receptors PET 18 F-fluorodeoxyglucose (FDG)-in advanced cases 6-[ 18 F]- fluorodopamine - excellent sensitivity

21. 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

22. Preop workup CBC, electrolytes, creatinine , INR/PTT CXR EKG Echo (r/o DCM )

23. 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!

24. 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

25. 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 )

26. 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)

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

28. 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

29. 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

30. 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

31. 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

32. 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

33. 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

34. Pheo : Unresectable , Malignant -blockade Selective  1 -blockers (Prazosin, Terazosin, Doxazosin) 1 st line as less side-effects Phenoxybenzamine: more complete -blockade -blocker CCB, ACE-I, etc. Nuclear Medicine Rx: Hi dose 131 I-MIBG or 111 indium-octreotide depending on MIBG scan or octreoscan pick-up Sensitize tumor with Carboplatin + 5-FU

35. Pheo & Pregnancy Diagnosis with 24h urine collections and MRI No stimulation tests, no MIBG if pregnant 1 st & 2 nd trimester (< 24 weeks): Phenoxybenzamine + blocker prep Resect tumor ASAP laprascopically 3 rd trimester: Phenoxybenzamine + blocker prep When fetus large enough: cesarian section followed by tumor resection