Overview
Definition:
Pheochromocytoma is a neuroendocrine tumor arising from chromaffin cells of the adrenal medulla, or from extra-adrenal paraganglia
It secretes excessive catecholamines (epinephrine, norepinephrine, dopamine), leading to paroxysmal or sustained hypertension and other systemic manifestations.
Epidemiology:
Rare tumor, occurring in approximately 0.1-0.2% of hypertensive patients
Incidence is 1-2 cases per million person-years
Can occur at any age, with a peak incidence in the third to fifth decades
About 10% are familial (associated with MEN 2A, MEN 2B, VHL syndrome, NF-1, SDHB/C/D mutations)
10% are malignant and 10% are extra-adrenal (paragangliomas).
Clinical Significance:
Pheochromocytoma is a surgically curable cause of secondary hypertension
Uncontrolled secretion of catecholamines can lead to severe cardiovascular complications, including hypertensive emergencies, myocardial infarction, stroke, arrhythmias, and pulmonary edema
Proper diagnosis and management, especially perioperative hemodynamic control, are critical to prevent life-threatening events during surgical resection.
Clinical Presentation
Symptoms:
Classic triad: episodic headaches
Palpitations
Profuse sweating
Other symptoms include: anxiety, tremor, pallor, chest pain, dyspnea, abdominal pain, nausea, vomiting, weight loss
Symptoms can be paroxysmal (lasting minutes to hours) or sustained
Precipitating factors for attacks include: physical exertion, emotional stress, certain medications (e.g., beta-blockers, decongestants), positional changes, or induction of anesthesia.
Signs:
Hypertension (paroxysmal or sustained, often severe and resistant to conventional therapy)
Tachycardia or bradycardia (due to baroreceptor reflex)
Pallor
Tremulousness
Fever
Wide pulse pressure
Funduscopic changes of hypertensive retinopathy
In rare cases, signs of shock or congestive heart failure.
Diagnostic Criteria:
Diagnosis is confirmed by biochemical testing demonstrating excessive catecholamine and/or metanephrine secretion
No specific diagnostic criteria exist beyond biochemical confirmation and imaging
The World Health Organization (WHO) classification of endocrine tumors can be used for histopathological grading of resected tumors.
Diagnostic Approach
History Taking:
Detailed history focusing on the frequency, duration, triggers, and associated symptoms of paroxysmal episodes
Ask about family history of endocrine tumors, hypertension, or genetic syndromes
Inquire about prior diagnoses of anxiety disorders, panic attacks, or resistant hypertension
Review of medications is crucial to identify potential precipitating agents.
Physical Examination:
Careful assessment of vital signs, including blood pressure in both arms and orthostatic measurements if tolerated
Auscultate for abdominal bruits
Palpate for abdominal masses or hepatosplenomegaly
Perform a thorough cardiovascular and neurological examination
Ophthalmoscopic examination to assess for hypertensive retinopathy.
Investigations:
Biochemical tests are paramount: 24-hour urinary fractionated metanephrines and catecholamines (sensitivity >90%, specificity >85% for abdominal CT/MRI)
Plasma free metanephrines (more sensitive than urinary tests)
Clonidine suppression test or oral glucose tolerance test (OGTT) for equivocal cases
Imaging: CT scan or MRI of the abdomen and pelvis to localize the tumor
123I-MIBG scintigraphy or somatostatin receptor scintigraphy for metastatic disease or difficult-to-localize tumors
Consider genetic testing for hereditary syndromes.
Differential Diagnosis:
Essential hypertension, anxiety/panic disorder, hyperthyroidism, carcinoid syndrome, drug-induced hypertension (e.g., sympathomimetics, SSRIs), renal artery stenosis, hyperaldosteronism, Cushing's syndrome, other intra-abdominal masses.
Management
Initial Management:
Prior to definitive treatment, meticulous medical preparation is essential to prevent catecholamine-induced hypertensive crisis during anesthesia and surgery
Surgical removal is the definitive treatment for symptomatic pheochromocytoma.
Medical Management:
The cornerstone is pharmacologic blockade of catecholamine effects
Start alpha-adrenergic blockade at least 7-14 days preoperatively
Phenoxybenzamine (irreversible, non-selective alpha-blocker): typically 10-20 mg orally twice daily, titrated up to 40-60 mg twice daily
Prazosin, terazosin, doxazosin (selective alpha1-blockers): start at low doses and titrate up
Beta-blockers are initiated ONLY after adequate alpha-blockade has been established to prevent unopposed alpha-stimulation leading to reflex tachycardia or malignant hypertension
Propranolol, metoprolol: start at low doses (e.g., 10-20 mg TID) and titrate as needed, typically after 2-3 days of alpha-blockade
Calcium channel blockers (e.g., nifedipine) or ACE inhibitors may be used as adjuncts if BP is not controlled despite alpha/beta blockade, but are not first-line agents.
Surgical Management:
Surgical resection of the tumor is the definitive treatment
Laparoscopic adrenalectomy is the preferred approach for most adrenal pheochromocytomas
Open adrenalectomy may be necessary for very large tumors, invasive disease, or contraindications to laparoscopy
For extra-adrenal pheochromocytomas, surgical excision of the tumor and involved structures is performed
The surgical approach is chosen based on tumor location, size, and extent of invasion
Preoperative preparation must ensure adequate alpha and beta blockade
Anesthesia should be initiated with caution, and agents that can trigger catecholamine release should be avoided.
Supportive Care:
Intensive perioperative monitoring is crucial
This includes continuous ECG, invasive arterial blood pressure monitoring, central venous pressure monitoring, and pulse oximetry
Patients should be monitored for hypotension post-resection due to catecholamine depletion and volume shifts
Fluid resuscitation and vasopressors may be required
Postoperative hyperglycemia should be managed
Patients with malignant pheochromocytoma may require adjuvant chemotherapy or radiotherapy.
Intraoperative Hemodynamic Control
Preanesthetic Preparation:
Administer alpha-blockade for at least 7-14 days preoperatively
Titrate beta-blockade to control tachycardia (target HR >60 bpm) only after adequate alpha-blockade is achieved
Ensure adequate oral intake and volume status
Avoid medications that can trigger catecholamine release (e.g., certain anesthetics, sympathomimetics).
Anesthesia Induction:
Use balanced anesthesia techniques
Agents such as etomidate or ketamine (use with caution due to sympathetic stimulation) may be considered
Avoid pancuronium, as it can cause tachycardia
Ensure adequate depth of anesthesia before surgical manipulation.
Surgical Manipulation:
Sudden surges in blood pressure and heart rate are common during tumor manipulation, especially before ligation of tumor vascular pedicle
Continuous intravenous infusion of short-acting vasodilators like sodium nitroprusside or nitroglycerin is essential for immediate BP control
Labetalol or esmolol can be used for tachycardia or hypertension
Prepare for rapid fluid administration.
Tumor Excision And Postexcision:
After tumor ligation, rapid and profound hypotension can occur due to withdrawal of circulating catecholamines and the vasodilated state
Aggressive fluid resuscitation is often required
Norepinephrine or other vasopressors may be needed to maintain adequate blood pressure
Monitor for arrhythmias, myocardial ischemia, and cerebrovascular events.
Monitoring And Management Of Hypotension:
Continuous invasive hemodynamic monitoring is critical
Transesophageal echocardiography may be helpful in assessing cardiac function
Gradual withdrawal of vasopressors as the patient's vascular tone recovers
Management of post-operative arrhythmias and electrolyte imbalances is also vital.
Complications
Early Complications:
Hypertensive crisis (perioperative or postoperative)
Hypotensive shock post-resection
Arrhythmias (tachycardia, bradycardia, atrial fibrillation, ventricular arrhythmias)
Myocardial infarction
Stroke
Pulmonary edema
Renal failure
Wound complications
Adrenal insufficiency (rare with unilateral adrenalectomy if contralateral adrenal is healthy).
Late Complications:
Recurrence of pheochromocytoma (especially with incomplete excision or multifocal disease)
Metastatic disease (in malignant pheochromocytoma)
Long-term cardiovascular sequelae from prolonged hypertension
Development of diabetes mellitus
Hypertension may persist even after successful tumor removal if underlying vascular damage has occurred.
Prevention Strategies:
Meticulous preoperative medical management with alpha and beta blockade
Careful anesthetic management and avoidance of triggering agents
Judicious surgical technique
Thorough intraoperative hemodynamic monitoring and readiness to manage both hypertensive crises and hypotension
Adequate fluid resuscitation and judicious use of vasopressors post-resection
Long-term follow-up for recurrence and cardiovascular health.
Prognosis
Factors Affecting Prognosis:
Tumor size, malignancy, presence of metastases, completeness of surgical resection, and patient's overall cardiovascular health
Familial syndromes can be associated with multifocal disease and higher recurrence rates
Age and comorbidities also play a role.
Outcomes:
Benign pheochromocytomas are curable with complete surgical resection, with normalization of blood pressure in most cases
Malignant pheochromocytomas have a poorer prognosis, with 5-year survival rates ranging from 40-60%
Even after successful surgery, some patients may have persistent hypertension due to pre-existing vascular damage.
Follow Up:
Patients should undergo lifelong biochemical surveillance for recurrence (plasma free metanephrines or 24-hour urinary metanephrines/catecholamines annually for at least 5-10 years, or indefinitely)
Imaging surveillance may also be indicated
Regular monitoring of blood pressure and cardiovascular risk factors is essential
Genetic counseling and screening of at-risk family members are important for hereditary forms.
Key Points
Exam Focus:
Perioperative management is paramount for pheochromocytoma surgery
Alpha-blockade is essential preoperatively (at least 7-14 days)
Beta-blockade only after adequate alpha-blockade
Sudden hypotension post-excision is common and requires aggressive fluid resuscitation and vasopressors
Biochemical confirmation precedes imaging.
Clinical Pearls:
Never give a beta-blocker before adequate alpha-blockade in pheochromocytoma
Be prepared for catecholamine surges during tumor manipulation and profound hypotension post-excision
Consider pheochromocytoma in patients with refractory hypertension, episodic symptoms, or a family history of endocrine tumors.
Common Mistakes:
Inadequate preoperative medical preparation leading to intraoperative hypertensive crisis
Administering beta-blockers too early or without adequate alpha-blockade
Underestimating the potential for severe hypotension after tumor removal
Relying solely on imaging without biochemical confirmation
Delaying surgery due to fear of perioperative complications.