Phaeochromocytoma

A 35-year-old man presents to the emergency department with episodic headaches, sweating, and palpitations. His blood pressure is markedly elevated at 200/120 mmHg. During these episodes, he experiences anxiety and a sense of impending doom.

Pathophysiology

Phaeochromocytomas are tumours arising from chromaffin cells, which are neuroendocrine cells derived from the neural crest. These tumours typically originate in the adrenal medulla, the inner part of the adrenal gland.

  • Chromaffin cells produce and secrete catecholamines, primarily adrenaline and noradrenaline.
  • Phaeochromocytomas cause excessive and often uncontrolled release of these catecholamines, leading to the characteristic clinical manifestations of the disease.
  • Catecholamines have potent effects on the cardiovascular system, stimulating both alpha and beta-adrenergic receptors.
    • Alpha-adrenergic stimulation causes vasoconstriction, leading to increased blood pressure.
    • Beta-adrenergic stimulation increases heart rate and contractility, further contributing to hypertension.

Aetiology

Most phaeochromocytomas (approximately 90%) are sporadic, i.e. randomly without a known genetic cause. However, about 10% are associated with hereditary cancer syndrome that can predispose to phaeochromocytoma development:

  • Multiple endocrine neoplasia type 2 (MEN2A and MEN2B): These syndromes are characterized by tumours in multiple endocrine glands, including the thyroid, parathyroid, and adrenal glands. Phaeochromocytomas are a common feature of MEN2, often occurring bilaterally.
  • Von Hippel-Lindau disease (VHL): This disorder is associated with the development of various tumours, including haemangioblastomas in the brain and spinal cord, retinal angiomas, renal cell carcinomas, and phaeochromocytomas. Phaeochromocytomas occur in about 20% of VHL families and are often bilateral.
  • Neurofibromatosis type 1 (NF1): While phaeochromocytomas are less common in NF1 than in MEN2 or VHL, they can still occur. NF1 primarily affects the nervous system, causing benign tumours (neurofibromas) to grow on nerves. Other features include café-au-lait spots (light brown skin patches), Lisch nodules (pigmented iris hamartomas) and skeletal abnormalities.
  • Succinate dehydrogenase (SDH) mutations: Mutations in genes encoding subunits of the SDH complex, particularly SDHB, are strongly associated with phaeochromocytomas and paragangliomas. These mutations are often associated with a higher risk of malignancy and extra-adrenal tumours.

Epidemiology & Risk Factors

  • Phaeochromocytomas are rare, affecting an estimated 2-8 individuals per million people each year.
  • They can occur at any age but are most commonly diagnosed between the ages of 20 and 50.
  • There appears to be no gender predilection for sporadic phaeochromocytomas. However, some studies suggest that malignant phaeochromocytomas might be more common in women.
  • The presence of one of the genetic syndromes mentioned above significantly increases the risk of developing a phaeochromocytoma. Family history is a crucial factor in identifying individuals who might be at risk.

Clinical Features

The classic triad of symptoms for phaeochromocytoma is episodic headache, sweating, and tachycardia. However, the clinical presentation can be quite variable, and some individuals may have few or no symptoms.

General:

  • Sweating: This is a very common symptom, occurring in over 80% of cases.
  • Heat intolerance
  • Pallor or flushing: The sources note that pallor is more typical of phaeochromocytoma, unlike the flushing seen in carcinoid syndrome.
  • Feeling of apprehension or anxiety: This can be quite pronounced during paroxysmal episodes.
  • Pyrexia
  • Weight loss
  • Hyperglycaemia: Catecholamines can increase blood glucose levels.

Neurological:

  • Headache: Headaches are a hallmark symptom, typically described as throbbing or constant.
  • Paraesthesiae
  • Visual disturbances
  • Seizures

Cardiovascular:

  • Palpitations: Also very common, occurring in about 65% of cases.
  • Hypertension: The most prominent sign, often resistant to conventional antihypertensive treatment. Hypertension can be sustained or episodic (paroxysmal). It is important to note that some phaeochromocytomas can present with hypotension, particularly those secreting dopamine.
  • Chest pain
  • Dyspnoea
  • Postural hypotension: This is a less common finding but can occur due to decreased plasma volume.

Gastrointestinal:

  • Abdominal pain and nausea
  • Constipation: Can contribute to abdominal pain

Investigations

Biochemical Tests:

  • 24-hour urinary catecholamines and metanephrines:  Measuring urinary metanephrines (metanephrine and normetanephrine) is the most sensitive and specific test for diagnosing phaeochromocytoma. Metanephrines are metabolites of catecholamines and are more stable in urine, making them more reliable than measuring catecholamines directly.
  • Plasma metanephrines: Measuring plasma metanephrines can also be helpful, particularly in patients who are at high risk for phaeochromocytoma (e.g. those with familial syndromes).
  • Other tests:
    • Electrolytes: Hypokalaemia can occur, especially in cases with prolonged hypertension.
    • Glucose: Hyperglycaemia may be present due to the metabolic effects of catecholamines.
    • ECG: May show arrhythmias or signs of left ventricular hypertrophy.

Imaging Studies:

  • CT or MRI of the abdomen: These imaging modalities are used to localise the tumour once biochemical tests have confirmed catecholamine excess. CT is generally preferred because it is more widely available and less expensive. However, MRI may be better at visualising extra-adrenal tumours.
  • MIBG scan (metaiodobenzylguanidine scan): This is a specialised nuclear medicine scan that uses a radioactive tracer (MIBG) that is taken up by chromaffin cells. MIBG scans are particularly useful for detecting small or extra-adrenal tumours, as well as metastases. However, certain drugs (e.g. tricyclic antidepressants, sympathomimetics, labetalol) can interfere with MIBG uptake and should be discontinued before the scan.
  • Other imaging:
    • Chest X-ray: May show evidence of metastases, as approximately 10% of phaeochromocytomas are malignant.
    • Echocardiogram: Can be used to assess left ventricular function and may occasionally identify a mediastinal paraganglioma.

Genetic Testing:

  • Genetic testing is recommended for individuals suspected of having a hereditary phaeochromocytoma syndrome, especially those with a family history of the disease, bilateral or multifocal tumours, early age at presentation, or malignant disease.

Management

The management of phaeochromocytoma requires a multidisciplinary approach, involving endocrinologists, surgeons, and anaesthesiologists. The primary treatment is surgical removal of the tumour (adrenalectomy). However, careful preoperative preparation is essential to minimise the risks associated with catecholamine surges during surgery.

Preoperative Management:

  • Blood pressure control:
    • Alpha-adrenergic blockade is the cornerstone of preoperative management. Phenoxybenzamine, a long-acting, non-selective alpha-blocker, is the drug of choice.  It is crucial to start alpha-blockade before beta-blockade to avoid unopposed alpha-adrenergic stimulation, which can lead to a paradoxical increase in blood pressure.
    • Beta-blockade can be added after alpha-blockade is established, particularly in patients with tachycardia, arrhythmias, or heart disease.
    • Adequate fluid resuscitation is essential as patients with phaeochromocytoma are often volume-depleted due to the vasoconstrictive effects of catecholamines.
  • Other medications:
    • Calcium channel blockers: May be used in conjunction with alpha-blockers to control blood pressure.
    • Magnesium sulfate: May be used to prevent or treat catecholamine-induced arrhythmias.

Surgical Resection:

  • Laparoscopic adrenalectomy is the preferred surgical approach for most phaeochromocytomas, as it is minimally invasive and associated with shorter recovery times.
  • Open adrenalectomy may be necessary for larger tumours or those that are difficult to access laparoscopically.
  • Careful intraoperative monitoring is crucial to manage fluctuations in blood pressure and heart rate.
  • Postoperative hypotension can occur after tumour removal and is usually managed with fluid replacement.

Medical Management:

  • Medical management with alpha- and beta-blockers may be used in patients who are not surgical candidates (e.g. those with metastatic disease) or as a bridge to surgery.
  • Other medications, such as metyrosine (an inhibitor of catecholamine synthesis), may be considered in select cases.

Malignant Phaeochromocytoma:

  • Complete surgical resection is often not possible for malignant phaeochromocytomas. Treatment options include:
    • Debulking surgery: To remove as much of the tumour as possible.
    • Radiotherapy: To target residual tumour or metastases.
    • Chemotherapy: To slow tumour growth.
    • Targeted therapies: Newer therapies, such as VEGF inhibitors (e.g. sunitinib), are being investigated for the treatment of malignant phaeochromocytoma.

Complications & Prognosis

Untreated phaeochromocytoma can lead to serious, life-threatening complications, including:

  • Hypertensive crises: These are sudden, severe elevations in blood pressure that can cause:
    • Stroke
    • Myocardial infarction
    • Heart failure
    • Aortic dissection
    • Retinal haemorrhage
    • Encephalopathy
  • Arrhythmias: Catecholamines can trigger various cardiac arrhythmias, including:
    • Atrial fibrillation
    • Ventricular tachycardia
    • Ventricular fibrillation
  • Cardiomyopathy: Chronic exposure to high levels of catecholamines can lead to heart muscle damage and dysfunction.
  • Metabolic complications: Hyperglycaemia, hypokalaemia, and metabolic alkalosis can occur.
  • Malignant transformation: While most phaeochromocytomas are benign, approximately 10% are malignant.

Prognosis:

  • The prognosis for benign phaeochromocytoma is generally excellent after surgical resection, with a 5-year survival rate of over 95%.
  • The prognosis for malignant phaeochromocytoma is significantly worse, with a 5-year survival rate of around 40%.

Long-term Follow-up:

  • Lifelong follow-up is recommended for all patients with phaeochromocytoma, even after successful surgical resection, to monitor for recurrence or the development of metastases.
  • Regular blood pressure monitoring and biochemical testing are essential components of long-term care.