Pheochromocytoma

Sub-section: Adrenal Section: Endocrine

Definition

• Tumors derived from Chromaffin cells
  • Neural crest origin
  • Pheochromocytoma from Adrenal Medulla
  • Paragangliomas from Autonomic Ganglia

Incidence

• 3-8 per million per year
• Middle age most common (40-50)
• Hereditary forms can occur at younger age
• Very rare in children
• 0.2% of hypertensive patients
• M = F
• Traditionally the “10%” tumour - not true anymore
  • 10% bilateral
  • 10% extra-adrenal
  • 10% familial
  • 10% malignant

Clinical Presentation

• 5% found as incidentalomas (“pre-symptomatic”)
• Symptoms due to excessive catecholamine secretion
  • Classic Triad
    • Headaches
    • Palpitations
    • Diaphoresis (sweating)
  • Pallor, nausea, weight loss, tiredness, anxiety
  • Characteristically paroxysmal, intermittent, non-specific + overlap with other conditions
• Diagnosis difficult and delayed
• Signs
  • Hypertension (in 90%)
    • But only 0.5% of patients with hypertension and suggestive symptoms actually end up having phaeochromocytoma
  • Diabetes mellitus
  • Pheochromocytoma crisis (massive catecholamine release)
    • Sudden death, arrhythmia, heart failure, multi-organ failure, CVA
    • Can be precipitated by anaesthesia, trauma, biopsy, haemorrhage, tumor manipulation

Aetiology

• Majority sporadic
• Up to 1/3 carry germ line mutations, main ones include:
  • RET gene mutation (MEN 2 syndrome A/B)
    • Phaeochromocytomas occur in half of MEN 2 pts
  • VHL gene mutation (in Von-Hippel-Lindau disease)
    • Phaeochromocytomas in up to 1/3
    • CNS hemangioblastoma
    • Renal cell cancer
    • Cysts in kidney, testes, pancreas
  • NF1 gene mutation (in Neurofibromatosis Type 1)
  • Paraganglioma syndrome (SDH B, SDH C)
    • Paraganglioma/ Phaeochromocytoma syndrome
    • Particularly high risk of malignancy
  • Family hx important as new diagnosis may be first indication of familial syndrome
  • Hereditary gene mutations more likely to be young (< 50), multiple tumors, bilateral, extra-adrenal

Biochemical Workup

• Plasma metanephrines
  • Single blood test, good initial screen to R/O Phaeochromocytoma
  • Highly sensitive (95-98)
  • Specificity only (85-89%)
  • Plasma catecholamine measurement poor indicator
    • Levels vary episodically, can be elevated for other reasons
  • Due to rare nature of phaeochromocytoma, false positive to true positive ratio is 30:1
• 24hr Urinary Metanephrines and Catecholamines
  • More cumbersome than single blood test
  • Gives more stable measurement over time
  • Use to confirm diagnosis if plasma metanephrines raised
  • Many confounding medications
  • Discontinue sympathomimetics, phenoxybenzamine, acetaminophen, psychotropic drugs
• If still equivocal – Clonidine suppression test

Localisation

• No role for adrenal venous sampling (high false positive)
• No role for biopsy – may precipitate severe HTN or make operating more difficult

Cross-sectional Imaging

• MRI – more sensitive
• CT – often yields more anatomic definition for operative planning
• Specificity for both only 70%
  • Due to high prevalence of adrenal incidentalomas

MIBG Scintigraphy

• Use next if multifocal disease suspected or if tumour can’t be seen on CT/MRI
• MIBG = Meta-IodoBenzylGuanidine – Radioactive tracer
  • Noradrenaline analogue
• Highly specific, but sensitivity only 77-90%

DOTA-TATE or FDG PET

• Highly sensitive, superior to MIBG

Peri-op Medical Management

• Aim to counteract haemodynamic changes
• Intra-operative hypertension
• Post-operative hypotension

Pre-op elective management

• Phenoxybenzamine
  • Long-acting non-selective, non-competitive α–adrenergic receptor antagonist
  • Start low and increase over 2-4 weeks
• Alternatives
  • Doxazosin, Urapidil
  • CCB’s (nicardipine)
• β-blockers for tachycardia/arrhythmia
  • Only after α–blockade
  • Unopposed α- action can precipitate hypertensive crises and pulmonary oedema!

Unopposed Alpha Stimulation

• Acute increase in blood pressure and coronary vasoconstriction after administration of a beta-blocker
  • Normal mechanism - stimulation of:
    • Alpha-1 receptors
      • Smooth muscle contraction and vasoconstriction
    • Beta-1-receptors
      • Increases cardiac conduction, HR, and contractility
    • Beta-2-receptors
      • Smooth muscle relaxation
    • Vascular tone is usually mediated by a balance of alpha-1 contraction and beta-2 relaxation
• Non-selective beta-blockade will
  • Inhibit beta-2 relaxation effects (with ongoing alpha-1 stimulation)
    • ⇒ Vasoconstriction and hypertensive crisis, with coronary artery vasoconstriction
  • Inhibit beta-1 effects
  • Causes increased end diastolic pressure, increased cardiac fibre length
  • Increases BP and ventricular contraction (Frank-Staling law)

Intra-operative Planning

• Arterial line and central lines to detect and correct potential hypertensive episodes
• Avoid undue handling of tumor
• If hypertensive episode, use:
  • Sodium nitroprusside (short acting vasodilator)
  • Nicardipine (CCB)
  • Phentolamine (α–adrenergic receptor antagonist)
  • PLUS Beta-blockers for tachycardia/arrhythmia

Post-operative Management

• Excess catecholamines cause vasoconstriction and state of hypovolaemia
  • Once tumor devascularised, fall in catecholamines
  • Leads to peripheral arteriolar vasodilation and large increase in venous capacitance
    • Can lead to cardiovascular collapse
  • Aggressive volume replacement/inotropes may be needed
  • Consider HDU/ICU post-op
  • Monitor BSLs
    • Hypoglycemia due to withdrawal of lipolytic, glycolytic, and glycogenolytic effects

Surgical Management

• Procedure of choice is Laparoscopic Adrenalectomy
  • Paragangliomas may need open resection
• Tumours tend to be highly vascular and adhere to adjacent structures
• Laparoscopy contraindicated when imaging evidence of local invasion

GAPP score

• The Grading of Adrenal Pheochromocytoma and Paraganglioma (GAPP) is a tool for risk stratification for predicting metastasis and the prognosis of patients.
  • Currently, all Paragangliomas/Pheochromocytoma are believed to have some metastatic potential and are assigned malignant tumors (ICD-O/3) by the WHO Classification of Endocrine Organs (2017, 4th edition). Therefore, the previous categories benign and malignant PPGL have been eliminated in favor of risk stratification approach.
• PASS
  • Phaeos only
  • Dated now - not used
• GAPP
  • Phaeos and paragang
  • Histology and clinical

• This allows risk stratification as below

Malignant Phaeochromocytoma

• All have malignant potential ! - re classified
• 2.5-40% are malignant, depending on genotype
• 5yr survival 20-45%
• Incidence higher if:
  • Larger
  • Extra-adrenal (paragangliomas)
  • Paraganglioma syndrome B mutation carriers
• Histopathologic features don’t differentiate benign or malignant
  • Diagnosis of malignancy based on metastatic disease
    • Must be to locations which neuroectodermal tissues NOT normally found!
      • Axial skeleton, LNs, Liver, Lung, Kidney
• Imaging
  • DOTATE
• If unresectable
  • Consider α- and β- blockade
  • Tumor debulking can give symptom relief
  • Palliative radiotherapy, chemotherapy, RFA, TACE may have roles
  • Therapeutic MIBG can produce symptomatic and hormonal improvement + some tumour regression

Pheochromocytoma in Pregnancy

• Rare but dangerous
• Significant mortality for mother and infant
  • α- blockade, elective 3rd trimester C-section
• Vaginal delivery contraindicated
• Early post-partum adrenalectomy