Pheochromocytoma

Pheochromocytoma

Anesthetic relevance	Critical
Anesthetic management	{{{anesthetic_management}}}
Specialty	Endocrinology
Signs and symptoms	Hypertension Headache Diaphoresis Tachycardia
Diagnosis	Urine metanephrines and catecholamines Abdominal CT/MRI for localization
Treatment	Surgical resection Alpha/beta blockade
Article quality
Editor rating	Comprehensive
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Pheochromocytoma is a rare neuroendocrine disease of the adrenal gland where catecholamine-secreting tumors cause hypertension. Pheochromocytoma is present in 0.05% - 0.2% of hypertensive individuals, the incidence of the disease presents equally between men and women with a distribution across age groups but peaks in between 40 and 50 years of age. The classic presentation of the disease is a triad of symptoms including headache, palpitations, diaphoresis with a documented clinical sign of hypertension (present in 90% of patients with pheochromocytoma). However, patients can often present with less definitive symptoms such as tremor, anxiety, flushing, weight loss, and hyperglycemia. While the majority of pheochromocytoma emerges from adrenal tumors, roughly 15-20% can be extra-adrenal in etiology.

Pathophysiology

• Pheochromocytoma and paragangliomas are rare-catecholamine-secreting-neuroendocrine tumors. Most of these tumors are derived from chromaffin cells located in the adrenal medulla, but around 15-20% are extra-adrenal in etiology with possible sites including paraganglia of sympathetic chain, paraaortic, and organ of zuckerkandl (aortic bifurcation). Those that arise from within the adrenal medulla are called “pheochromocytomas” whereas those that derive from outside the adrenal gland are called “paragangliomas”.
• These tumors have the capacity to produce excessive quantities of catecholamines including epinephrine, norepinephrine, and dopamine. These catecholamines mediate their effects by alpha-1, alpha-2, beta-1, and beta-2 adrenergic subtype receptors.
  • Alpha-1 receptors primarily mediate smooth muscle contraction notably causing vasoconstriction and alpha-2 receptors primarily regulate sympathetic outflow by inhibiting norepinephrine, acetylcholine, and insulin release.
  • Beta-1 receptors primarily increase heart rate and contractility and beta-2 receptors mediate smooth muscle relaxation notably causing vasodilation and bronchodilation.
• The net result of the adrenergic receptor activity is increased blood flow and oxygen delivery to the brain.
• Excessive catecholamine levels in pheochromocytoma can activate these receptors resulting in the classic symptoms including hypertension, tachycardia, headache and diaphoresis.
• Most cases of pheochromocytoma are sporadic. However, around 40% of cases have an association with familial syndrome including multiple endocrine neoplasia type 2 (MEN2), Von Hippel-Lindau syndrome, and neurofibromatosis type 1.
• The familial association may be linked to mutations in succinate dehydrogenase, a protein located in the mitochondria that is critical in oxidative phosphorylation.

Signs and symptoms

Signs and symptoms of pheochromocytoma are related to the excessive catecholamine levels. Symptoms are present in approximately half of patients with pheochromocytoma and paragangliomas. Due to the episodic nature of catecholamine synthesis and release, the symptoms are typically paroxysmal rather than continuous.

The classic triad of symptoms include episodic headache, diaphoresis, and tachycardia although not all patients will experience all three symptoms. Less than 50% of patients experience paroxysmal hypertension.

There are also other common nonspecific manifestations of pheochromocytoma include:

• Orthostatic hypotension
• Pallor
• Tremor
• Weight-loss
• Generalized Weakness
• Visual blurring
• Papilledema
• Hyperglycemia
• Dyspnea
• Constipation
• Cardiomyopathy
• Psychiatric Manifestations
  • Anxiety
  • Panic attacks

Rarely, patients can present with “pheochromocytoma crisis” which manifests with hypertension or hypotension, hyperthermia, mental status change, and other organ dysfunction.

Diagnosis

Diagnosis of pheochromocytoma relies on measurement of excessive levels of catecholamines and its metabolites followed by imaging studies. Catecholamine hypersecretion can be confirmed by measurement of urinary and plasma catecholamines; and/or metanephrine and normetanephrine, metabolites of epinephrine and norepinephrine.

• 24 hour urine levels of these compounds have classically been used to diagnose pheochromocytoma and is the most reliable test.
  • Though the test may be inconvenient, it has high sensitivity and specificity.
  • 2-fold increase in the upper limit of normal of catecholamine or metabolites is defined as a positive result.
• Plasma metanephrine and normetanephrine is also commonly used for diagnosis but notably has a lower specificity (89%) than 24-hour urine levels.
  • Given the rare incidence rate of pheochromocytoma and the high false positive rate, plasma free metanephrine testing is mainly used as a screening tool to exclude rather than to confirm pheochromocytoma. When positive, confirmatory testing with urine levels is warranted.

When equivocal results occur, a clonidine suppression test can be used. Clonidine is an alpha-2 adrenergic antagonist and decreases catecholamine levels. In patients with pheochromocytoma, clonidine will fail to suppress the catecholamine levels.

Many drugs and conditions can affect the levels of catecholamines and its metabolites. Therefore it is important to minimize these confounding variables. Before these diagnostic tests, it is important to discontinue any interfering medications including sympathomimetics, tricyclic antidepressants, acetaminophen. Patients should also avoid caffeine, strenuous physical activity, and smoking 12 hours prior to testing. Plasma samples should also be drawn following 30 minutes of supine rest.

Imaging

Radiological evaluation follows biochemical confirmation to locate the tumor. 95% of pheochromocytomas are located within the abdomen and pelvis but 15% are extra-adrenal.

• Computed Tomography (CT) or magnetic resonance imaging (MRI) are usually performed first with a sensitivity of 88-100% and a lower specificity of 70% because of high prevalence of incidentalomas. MRI is slightly more sensitive than CT, but CT provides better tomographical definition.

• Iobenguane I-123 can be used in a setting of negative MRI or CT results but high clinical suspicion particularly for multifocal disease with a sensitivity of 85-88% and specificity of 70-100%. Iobenguane I-123 is a compound similar to norepinephrine that is taken up in adrenergic tissue like pheochromocytoma.

• Fludeoxyglucose-positron emission tomography (FDG-PET) and 68-Ga Dotatate PET are highly sensitive tests (74-100%) with best performance in metastatic disease. However, there is limited availability of these relatively newer modalities at academic centers.

Genetic Testing

Although most pheochromocytomas are sporadic, 40% are associated with familial disorders including multiple endocrine neoplasia type 2, Von Hippel-Lindau syndrome, and neurofibromatosis type 1. Typically, genetic testing is performed postoperatively after a pathological diagnosis.

Patients with pheochromocytoma should be engaged in shared decision making for genetic testing. Patients with paraganglioma should undergo succinate dehydrogenase mutation testing.

Contraindicated Diagnostic Procedure

• Selective Adrenal Venous Sampling may result in falsely positive catecholamine levels and subsequent inappropriate adrenalectomy.
• Ultrasound is not recommended given low sensitivity.

Treatment

Medication

The goal of preoperative medical optimization of pheochromocytoma is to normalize blood pressure and to expand contracted intravascular space.

• Alpha adrenergic blockade is started at least 7 days preoperatively and longer if patient suffered recent MI, cardiomyopathy, refractory hypertension
  • Non-selective alpha-adrenergic antagonist (Phenoxybenzamine) is the most commonly used for preoperative blockade
    • Dosing and Frequency
      • Initial dose 10 mg once or twice daily
      • Titrate up 10 to 20 mg in divided doses every two to three days as needed to max dose of 40 mg three times daily
    • Side effects: reflex tachycardia, postural hypotension, nasal congestion, marked fatigue, retrograde ejaculation
  • Selective alpha-1 adrenergic antagonist (Prazosin, Doxazosin, or Terazosin) may also be used though phenoxybenzamine provides most complete alpha-adrenergic blockade
    • Dosing and Frequency
      • Prazosin: 2-5 mg two or three times daily
      • Doxazosin: 2-8 mg daily
      • Terazosin: 2-5 mg daily
    • More favorable side effect profile and cheaper than phenoxybenzamine
  • Choosing between alpha-adrenergic antagonists is provider and institutional dependent.
• Beta Adrenergic blockade can be started after adequate alpha adrenergic blockade in patients with persistent tachycardia
  • A beta-blocker should never be used without an alpha-blocker because blockade of vasodilatory peripheral beta receptors with unopposed alpha adrenergic receptor stimulation can exacerbate hypertensive episodes
  • Selective beta-adrenergic antagonists (atenolol, metoprolol) are preferred over nonselective-beat adrenergic antagonists (propranolol) and are started usually 2-3 days preoperatively
    • Dosing and Frequency
      • Atenolol: 12.5-25 mg two or three times daily
      • Metoprolol: 25-50 mg three or four times daily
      • Propranolol: 20-80 mg once or twice daily
  • Cautious use if patient has asthma or congestive heart failure as patients are at risk of acute pulmonary edema with beta-blockade
• Combined Alpha and Beta Adrenergic Blockade (Labetalol or Carvedilol) can be used but is not the primary choice for blockade given the fixed ratio of alpha to beta antagonistic activity is suboptimal in controlling hypertensive episodes
• Calcium Channel Blocker (Amlodipine, Nicardipine, Nifedipine, Verapamil)
  • Although less effect than alpha-adrenergic blockers, calcium channel blockers are another option
  • Indications
    • Supplement adrenoceptor blockade for adequate blood pressure control
    • Severe side effects to adrenoceptor blockade
    • Prevent adrenoceptor-blockade sustained hypotension
  • Dosing and Frequency
    • Amlodipine: 10-20mg daily
    • Nicardipine: 60-90 mg daily
    • Nifedipine: 60-90 mg daily
    • Verapamil: 180-540 mg daily

Catecholamine Synthesis Inhibitors (Metyrosine)

• Metyrosine or alpha-methyl-L-tyrosine is an analog of tyrosine that competitively inhibits tyrosine hydroxylase, the rate limiting step in catecholamine synthesis.
• Though incompletely, it depletes catecholamine stores with maximum effect after around 3 days
• Disadvantages include limited availability and high-dose-side effects including depression, anxiety, galactorrhea, diarrhea
• Dosing and Frequency
  • 250 mg every 6 hours; may increase 250-500 mg daily; max: 4g daily
• Availability and utilization is institution dependent

Surgery

Surgical excision is the only curative treatment in patients with pheochromocytoma. This procedure is a variant of an adrenalectomy with a curative rate greater than 90%. Successful excision involves meticulously multidisciplinary planning amongst endocrinologists, surgical team, and anesthesiologists. Careful preoperative optimization and intraoperative management is critical to ensure hemodynamic stability during excision.

Per the United States Endocrine Society 2014 Clinical practice guideline for pheochromocytoma, a laparoscopic resection is recommended unless local invasion is present. Surgical approaches include laparoscopic transabdominal, laparoscopic retroperitoneal, or single incision laparoscopic retroperitoneal. Open approach may be warranted in extra-adrenal or locally-invasive disease.

Prognosis

• A number of factors can affect the prognosis including: location of tumor, metastatic status, size of tumor and age at initial presentation.
• During the early 20th century, the perioperative mortality of this disease ranged between 26-50%.
• As surgical technique and perioperative management has improved, the mortality has decreased to roughly 1% in specialized centers.
• The largest North American series published about pheochromocytoma excision described 108 cases, where 90% were conducted laparoscopically, and the perioperative morbidity rate was 13% with no mortalities.
• For non-metastatic and metastatic pheochromocytomas, the 5-year survival rate is 97% and 84%, respectively.

Epidemiology

• US prevalence of pheochromocytoma is between 1 in 2500 and 1 in 6500
• US incidence of pheochromocytoma is 500-1600 cases per year
• A majority of pheochromocytomas are sporadic whereas around 40% are familial and associated with disorders including multiple endocrine neoplasia type 2, Von Hippel-Lindau syndrome, and neurofibromatosis type 1.
  • Frequency of pheochromocytoma in familial disorders
    • Multiple Endocrine Neoplasia type 2: 50%
    • Von Hippel-Lindau syndrome: 10-20%
    • neurofibromatosis type 1: 2-3%
• Incidence of sporadic pheochromocytoma occur equally common in males and females but peaks in between 40 and 50 years of age
• Familial pheochromocytoma cases occur around 15 years earlier than sporadic cases.
• Amongst individuals with hypertension, 0.05% - 0.2% have pheochromocytoma.