Pheochromocytoma

• Pheochromocytomas are rare catecholamine-secreting tumors that develops in the adrenal medulla and secrete excess catecholamines, leading to potentially severe cardiovascular manifestations.
• A rare, usually benign, tumor that arises from the chromaffin cells of the sympathetic nervous system. The rule of 10% applies in pheochromocytoma with 10% being extraadrenal, 10% malignant, 10% in children, and 10% bilateral or multiple (>right side). Also, 10% are not associated with hypertension.

• Incidence
  • Most common tumor of the adrenal medulla in adults
  • Present in up to 1% of all hypertensive patients
• Age: 3rd–5th decades of life

• Pheochromocytomas can produce and release large quantities of catecholamines (eg, norepinephrine, epinephrine), which bind to alpha- and beta-adrenergic receptors, resulting in increased vascular resistance, tachycardia, and enhanced cardiac output.
  • Excessive alpha-receptor stimulation can cause severe vasoconstriction
  • Beta-receptor stimulation may lead to arrhythmias and hypermetabolism.
• Catecholamine release may occur intermittently or in response to physical or emotional stress, anesthesia, or certain medications.

• Most cases of pheochromocytoma are sporadic, but approximately 40% may be seen as part of genetic syndromes such as:
  • Multiple endocrine neoplasia type 2 ( table 1) and
  • von Hippel-Lindau disease (  table 2).

Age (commonly presents in the third to fifth decades of life) and family history are risk factors.

The classic triad associated with pheochromocytoma includes episodic headaches, sweating, and palpitations.  These episodes may be triggered by physical exertion, stress, or specific drugs.

• Headaches are often episodic and present in 90% of patients.
• Paroxysmal hypertension occurs in approximately 50% of patients and may be associated with orthostasis (possibly reflecting low plasma volume).  Sustained hypertension and hypertensive crises can also be seen.
• Paroxysms of diaphoresis and other manifestations of hyperadrenergic spells (eg, tremor, pallor, anxiety)

The classic triad is present in <50% of patients.

Because catecholamines inhibit insulin secretion, pheochromocytoma should also be considered in patients who develop hyperglycemia that is atypical for both type 1 and type 2 diabetes mellitus, especially when accompanied by other suggestive features.

Indications for diagnostic testing are presented in the table ( table 3).

• Biochemical assessment
  • Best initial test
    • ↑ free metanephrine level in plasma
  • Confirmation with 24-hour urine collection
    • ↑ vanillyl mandelic acid (breakdown of norepinephrine and epinephrine)
    • ↑ metanephrines (more sensitive than VMA)
• Histology
  
  • Chromaffin cells with enlarged dysmorphic nuclei ( image 1)
• If biochemical tests are abnormal, imaging (CT or MRI) is indicated to localize the tumor.
• Nuclear scintigraphy (eg, metaiodobenzylguanidine [MIBG] scan) can be used to localize small tumors if CT or MRI is negative.  MIBG resembles norepinephrine, is taken up by adrenergic tissue, and can detect tumors not detected by CT or MRI.  MIBG scans are also performed in patients with large tumors (>5 cm diameter) because they have a higher risk of malignancy and possible extraadrenal disease.  Younger patients and those with a familial disorder also require MIBG scan after initial CT or MRI as they have a higher risk of extraadrenal and multiple tumors.

Pheochromocytomas should undergo surgical resection due to the risk for complications caused by catecholamine surges and the potential for malignant disease.  However, surgical removal of a pheochromocytoma is a high-risk procedure because intraoperative catecholamine surges can precipitate hypertensive crisis, pheochromocytoma crisis (a condition characterized by labile blood pressures, high fever, and multiorgan failure), and fatal arrhythmias.

To help prevent these complications, appropriate adrenergic blockade is needed prior to surgery.  The order of administration of adrenergic blockade is critical.

• Beta-blocker therapy in the absence of alpha-adrenergic blockade can lead to lethal hypertensive crisis due to unopposed alpha-1 stimulation.  Therefore, alpha-adrenergic blockade should be administered first, usually 7-14 days prior to surgery.  Phenoxybenzamine, an irreversible and nonselective alpha blocker, is often preferred; however, selective alpha-1 blockers (eg, terazosin) are also sometimes used.  Patients should also be encouraged to increase sodium intake and stay well-hydrated to minimize possible side effects of alpha-adrenergic blockade (eg, orthostasis, hypotension).
• Once adequate alpha-adrenergic blockade is established, beta-adrenergic blockade (eg, propranolol) can be safely initiated, usually 2-3 days prior to surgery.

Complications can result from both the tumor itself and from surgical resection.

• Hypertensive crisis:  precipitated by catecholamine surges, which can lead to stroke, myocardial infarction, or pulmonary edema.
• Cardiomyopathy:  can result from prolonged or excessive catecholamine exposure.
• Metastasis:  occurs in malignant pheochromocytomas, most commonly affecting bones, liver, and lungs.

Even with adequate preoperative alpha blockade and adequate fluid replenishment, some patients with pheochromocytoma have intraoperative and postoperative complications.

• Hypotension is an important intraoperative complication due to decreased circulatory catecholamine levels following tumor removal.  In addition, persistent preoperative alpha blockade results in decreased vascular tone.  Intra- and postoperative hypotension usually responds well to normal saline bolus.  Pressors may be required in patients who do not respond to intravenous fluids.
• Other complications include hypertensive crisis, hypoglycemia, and cardiac tachyarrhythmias ( table 4).