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 gene Locus % malignant

RET 10q11.2 Rare

NF1 17q11.2 Rare

SDHD 11q23 Rare

SDHB 1p 50%

VHL 3p 5%

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

Biochemical testing

1. 24-hour urine catecholamines & metanephrines

2. Plasma metanephrines

Biochemical testing

test sensitivity specificity

24 hr urine catecholamines & metanephrines

88% 99%

Plasma metanephrines 96% 85%

JCEM. 2003;88(10):4533-9.

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

CT

Eur Radiol. 2007;17:2804-09.

CT

Eur Radiol. 2008;18:2885–92.

MRI

123I-MIBG

PET CT

18F-FDG (18F-fluoro-2-deoxy-D-glucose) 18F-FDA (18F-fluorodopamine) 18F-DOPA (18F-3,4-dihydroxyphenylalanine) 68Ga-DOTA-NOC (68Ga-[1,4,7,10-

tetraazacyclododecane-1,4,7,10-tetraacetic acid]-1-NaI3-octreotide)

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

PET CT

PET CT

MEN 2, VHL, SDHD

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

PET CT

68Ga-DOTA-NOC Pheochromocytoma (and paraganglioma)

also express somatostatin receptor (SSTR) Sensitivity = 100% Specificity = 85.7% Accuracy = 98%

Eur Radiol. 2012 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 α1-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 α1-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 endASIS

1st 12mm port

2nd 12mm port(camera)3rd 12mm port4th 5mm port

Head end

Foot end

Surgeon’sside

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 1st to 3rd years Annually after 4th year

History & physical examination Blood pressure Biochemical testing Regular imaging not suggested

Unresectable Disease

Blood pressure and symptom control Cytoreductive surgery Transarterial chemoembolization (TACE) 131I-MIBG 90Y/177Lu 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