Pheochromocytoma: A Literature Review Department of Surgery Queen Mary Hospital

Introduction Tumors arise from enterochromaffin cells in adrenal medulla Release of catecholamines and their metabolites: Epinephrine, norepinephrine, dopamine Metaneprhine, normetaneprhine

Introduction Paragangliomas: Abdomen – para-aortic region Thorax Head & neck

Thoracic Paraganglioma

Presentation 1. Classical symptoms: Headache, intense & global in nature (80%) Palpitation (64%) Diaphoresis (57%) 2. Secondary hypertension 3. Adrenal incidentaloma 4. Detected by screening in patients with predisposing syndromes

Genetic Abnormalities Genetic mutations known to associate with pheochromocytoma: VHL (von Hippel Lindau) RET (rearranged during tranfection) SDHB & SDHD (mitochondrial succinate dehydrogenase enzyme complex subunit B & D) NF1 (neurofibromin 1)

Genetic Abnormalities Mutated geneLocus% malignant RET10q11.2Rare NF117q11.2Rare SDHD11q23Rare SDHB1p50% VHL3p5%

Genetic Abnormalities Cluster 1: VHL, SDHB, SDHD increased intracellular concentration of HIF (hypoxia-induced factor) and angiogenesis Cluster 2: RET, NF1 increased activation of signaling pathway related to RNA synthesis & metabolism

Biochemical testing

1. 24-hour urine catecholamines & metanephrines 2. Plasma metanephrines

Biochemical testing testsensitivityspecificity 24 hr urine catecholamines & metanephrines 88%99% Plasma metanephrines96%85% JCEM. 2003;88(10):

Biochemical testing Precautions: Measure 24-hour urinary creatinine to ensure adequate urine sample Adequate rest before blood taking Withhold the following drugs: Labetalol Tricyclic antidepressants Buspirone  α-blockers, ß-blockers, diuretics, theophylline, levodopa

Biochemical testing Avoid the following clinical scenarios: Acute myocardial infarction Congestive heart failure, NYHA class 3 or 4 Cerebrovascular accidents Hypoglycaemia Alcohol withdrawal Other stress condition

Biochemical testing Tests not suggested for diagnosis of pheochromocytoma: Plasma catecholamines Urinary vanillylmandelic acid (VMA) Chromogranin A

Pharmacological testing Clonidine suppression test Glucagon stimulation test

Localization imaging CT MRI 131/123 I-MIBG (metaiodobenzylguanidine) PET CT with different tracers

CT Eur Radiol. 2007;17: CT

Eur Radiol. 2008;18:2885–92. MRI

123 I-MIBG

PET CT 18 F-FDG ( 18 F-fluoro-2-deoxy-D-glucose) 18 F-FDA ( 18 F-fluorodopamine) 18 F-DOPA ( 18 F-3,4-dihydroxyphenylalanine) 68 Ga-DOTA-NOC ( 68 Ga-[1,4,7,10- tetraazacyclododecane-1,4,7,10-tetraacetic acid]-1-NaI 3 -octreotide)

J Clin Endocrinol Metab. 2009;94(12):4757–4767. PET CT

MEN 2, VHL, SDHD J Clin Endocrinol Metab. 2009;94(12):4757–4767.

PET CT 68 Ga-DOTA-NOC Pheochromocytoma (and paraganglioma) also express somatostatin receptor (SSTR) Sensitivity = 100% Specificity = 85.7% Accuracy = 98% Eur Radiol Mar;22(3):710-9.

Medical therapy Purpose: Control blood pressure and heart rate Prevent intraoperative hypertensive crisis

Medical therapy Phenoxybenzamine (POB) Long acting, irreversible, non-selective α-blocker Reflex tachycardia & postoperative hypotension Prazosin, terazosin, doxazosin Selective α 1 -blocker  no reflex tachycardia Short acting  lower incidence of post-op hypotension

Medical therapy Calcium channel blockers Direct arteriolar smooth muscle relaxation No postural hypotension Prevent coronary vasospasm & myocarditis Use in combination with selective α 1 -blocker Surgery 106:1149–1154

Is pre-op alpha-blockade necessary? 30% of patients received no pre-medication No major cardiovascular complication

Surgical treatment Open Laparoscopic: Absolute contraindications: Excessive cardiopulmonary risks Relative contraindications: Large tumors Severe obesity Previous abdominal operations Malignant tumors

Positioning for Laparoscopic Approach

Head end Foot end ASIS

1 st 12mm port 2 nd 12mm port (camera) 3 rd 12mm port 4 th 5mm port Head end Foot end Surgeon’s side ASIS Xiphoid process Costal margin

Surgical treatment Intra-operative Hemodynamic Parameters UROLOGY 55(3):340-3

Surgical treatment Operative Outcome UROLOGY 55(3):340-3

Follow Up National Comprehensive Cancer Network (NCCN) guideline Every 6 months in 1 st to 3 rd years Annually after 4 th year History & physical examination Blood pressure Biochemical testing Regular imaging not suggested

Unresectable Disease Blood pressure and symptom control Cytoreductive surgery Transarterial chemoembolization (TACE) 131 I-MIBG 90 Y/ 177 Lu labeled octreotide Chemotherapy (CVD or temozolomide) Sunitinib

Future Prospects Diagnostic localization technique Genetic abnormalities Predicting malignant potential of primary tumour Treatment of unresectable disease

Conclusion Studying the genomics of pheochromocytoma aids early detection and development of novel therapy. Localization of metastatic lesions is improved by PET CT using new tracer nuclides. Management of pheochromocytoma require multidiciplinary approach.

Thank you

Biochemical testing Low risk group: Poorly controlled hypertension Incidentaloma with adrenocortical phenotype  24-hr urinary catecholamines & metanephrines High risk group: Personal/family history of pheochromocytoma Predisposing syndrome Vascular adrenal tumor on imaging  Plasma metanephrines