Pheochromocytoma originates from chromaffin tissue of the adrenal medulla, sympathetic ganglia, or other locations. It intermittently or continuously releases large amounts of catecholamines, leading to persistent or paroxysmal hypertension as well as functional and metabolic disruptions in multiple organs. Approximately 10% of these tumors are malignant. The condition is most commonly seen in individuals aged 20 to 50 years.
Tumor Locations and Biochemical Characteristics
Approximately 80–90% of pheochromocytomas are located in the adrenal glands, most frequently as unilateral tumors. A smaller proportion is bilateral, and multiple tumors are more common in children and familial cases. Extra-adrenal pheochromocytomas are referred to as paragangliomas, which may arise from the paravertebral sympathetic nerve chain in the thoracic, abdominal, or pelvic regions, or from parasympathetic ganglia associated with the glossopharyngeal and vagus nerves along the neck and skull base. These are mostly found in the abdomen, often near the abdominal aorta (accounting for approximately 10–15%) but may also occur in the thoracic cavity, neck, or intracranial regions. Extra-adrenal tumors often have multicentric origins and a higher rate of local recurrence.
Pheochromocytomas in the adrenal medulla predominantly produce norepinephrine and epinephrine, with norepinephrine being the primary product in the majority of cases. Rarely, only epinephrine is secreted, which is more typical in familial cases. Extra-adrenal pheochromocytomas, except for those arising from the aortic chromaffin bodies, produce only norepinephrine and lack the ability to synthesize epinephrine, as the conversion of norepinephrine to epinephrine by phenylethanolamine N-methyltransferase requires a high concentration of cortisol. This condition exists only in the adrenal medulla and the aortic chromaffin bodies.
Pheochromocytomas also produce a variety of peptide hormones, some of which may result in atypical symptoms such as facial flushing (vasoactive intestinal peptide, substance P), constipation (opioid peptides, somatostatin), diarrhea (vasoactive intestinal peptide, serotonin, motilin), pallor and vasoconstriction (neuropeptide Y), as well as hypotension or shock (vasoactive intestinal peptide, adrenomedullin). The tumor can also release chromogranin into the blood, which, upon elevation, can assist in diagnosis.
Clinical Manifestations
The clinical presentations of pheochromocytoma vary widely due to differences in tumor location, the quantity and type of catecholamines secreted, and the secretion pattern.
Cardiovascular System Manifestations
Hypertension
Hypertension is the most prominent symptom and presents either as paroxysmal or sustained hypertension. Sustained hypertension may also exhibit paroxysmal episodes.
Paroxysmal Hypertension
This is a characteristic presentation of pheochromocytoma. During an episode, blood pressure rises abruptly, with systolic pressure reaching 200–300 mmHg and diastolic pressure reaching 130–180 mmHg. This can be accompanied by severe headache, pallor, profuse sweating, tachycardia, a sense of tightness in the precordial region and upper abdomen, as well as symptoms such as chest pain, arrhythmia, anxiety, fear, nausea, vomiting, blurred vision, and diplopia. In severe cases, acute left ventricular failure or cerebrovascular accidents may occur. Following the cessation of an episode, symptoms such as facial flushing, skin warmth, excessive salivation, constriction of the pupils, and other signs of vagal excitation may appear. Triggers for these episodes include emotional stress, positional changes, smoking, trauma, urination, defecation, enemas, tumor palpation, anesthesia induction, and various drugs (e.g., histamine, guanethidine, glucagon, metoclopramide).
The duration of episodes is typically several minutes, but in some cases, it may last 1–2 hours or longer. The frequency of episodes may range from several times a day to once every few months. The triad of symptoms—hypertensive episodes accompanied by headache, palpitations, and excessive sweating—is particularly significant for the diagnosis of pheochromocytoma.
Sustained Hypertension
In cases of hypertension, pheochromocytoma should be considered under certain conditions. These include poor responsiveness to common antihypertensive drugs but effective response to α-receptor antagonists or calcium channel blockers, as well as symptoms of excessive sympathetic nervous system activation (e.g., profuse sweating, tachycardia), hypermetabolism (e.g., low-grade fever, weight loss), headache, anxiety, irritability, orthostatic hypotension, or significant blood pressure fluctuations. Orthostatic hypotension may result from insufficient circulating blood volume or reduced reflex vascular tone that maintains blood pressure in the upright position. In some patients (often children or adolescents), the disease may progress rapidly, manifesting as malignant hypertension with severe fundus damage, optic nerve atrophy, and even blindness within a short period. Complications such as azotemia, heart failure, and hypertensive encephalopathy may also occur. Urgent control of symptoms with anti-adrenergic agents and prompt surgical treatment may be required in these patients.
Hypotension and Shock
Some patients with pheochromocytoma may experience hypotension, or even shock, with alternating episodes of high and low blood pressure, along with signs of multi-organ dysfunction. The possible causes of hypotension and shock include:
- Sudden tumor hemorrhage or necrosis leading to the abrupt cessation of catecholamine release,
- Severe arrhythmias or heart failure caused by excessive catecholamines, which sharply reduce cardiac output,
- Predominant epinephrine secretion by the tumor, which activates β-receptors and dilates peripheral blood vessels,
- Intense vasoconstriction from excessive catecholamines, causing tissue hypoxia, increased microvascular permeability, and reduced blood volume,
- Secretion of multiple vasodilatory substances by the tumor.
Cardiac Manifestations
Excessive catecholamines may lead to catecholamine-induced cardiomyopathy and arrhythmias in some cases. Degenerative changes, necrosis, or inflammation of the myocardium may also occur. Myocardial damage may cause heart failure, while persistent severe hypertension may result in myocardial hypertrophy, cardiac enlargement, heart failure, or non-cardiogenic pulmonary edema. Electrocardiograms may reveal patterns indicative of transmural myocardial infarction.
Metabolic Disorders
Increased Basal Metabolism
Epinephrine may affect metabolic processes controlled by the central nervous system and the sympathetic nervous system, increasing oxygen consumption in patients. This heightened metabolism may lead to fever and weight loss.
Glucose Metabolism Disorders
Increased glycogenolysis and gluconeogenesis, combined with the inhibition of insulin secretion, may cause hyperglycemia and impaired glucose tolerance.
Lipid Metabolism Disorders
Accelerated fat catabolism may lead to elevated levels of free fatty acids in the blood.
Other Clinical Manifestations
Digestive System
Intestinal peristalsis and tone may be reduced, causing constipation or even intestinal dilation. Catecholamines may lead to proliferative and occlusive arteritis in the blood vessels of the gastrointestinal wall, resulting in intestinal necrosis, bleeding, or perforation. Catecholamines may also reduce gallbladder contraction, leading to bile stasis and gallstone formation.
Abdominal Tumor Mass
Approximately 15% of patients may present with a palpable abdominal mass. Tumor compression may induce blood pressure elevation.
Urinary System
Patients with prolonged or severe disease may experience renal impairment. In patients with pheochromocytoma located in the bladder, urination may trigger hypertensive episodes, bladder distension, or painless gross hematuria.
Hematologic System
Excessive catecholamines may decrease blood volume, redistribute blood cells, and increase peripheral white blood cell counts.
Concurrent Conditions
Pheochromocytoma may occur alongside genetic disorders caused by gene mutations, such as multiple endocrine neoplasia type 2 (RET gene mutations), neurofibromatosis type 1 (NF1 gene mutations), von Hippel-Lindau disease (VHL gene mutations), or familial paragangliomas associated with germline mutations in various subtypes of succinate dehydrogenase (SDH) genes. Hereditary pheochromocytomas are often multifocal and are prone to recurrence after surgical treatment.
Diagnosis and Differential Diagnosis
Early diagnosis of this condition is crucial. The tumor is typically benign and represents a curable form of secondary hypertension. Most patients can achieve normal blood pressure after tumor resection. However, undiagnosed cases pose significant potential risks, as hypertensive crises or shock may be triggered during medication administration, anesthesia, labor, surgery, or other scenarios. For patients with clinical indications of this condition, diagnostic evaluations include the following:
Measurement of Catecholamines and Their Metabolites in Blood and Urine
Elevated levels of catecholamines or their metabolites, such as metanephrine (MN), normetanephrine (NMN), and vanillylmandelic acid (VMA), in blood or urine are key diagnostic markers for pheochromocytoma. Among these, MN and NMN demonstrate the highest sensitivity and specificity. For patients with paroxysmal hypertension, catecholamine levels may remain normal at baseline but increase significantly after an episode. Therefore, measurements during the post-episode period are necessary. Ingestion of substances such as coffee, cola beverages, or medications like levodopa, labetalol, propranolol, and tetracycline may yield false-positive results. Elevations in endogenous catecholamines may also be caused by conditions such as shock, hypoglycemia, or increased intracranial pressure.
Pharmacological Testing
Pharmacological testing is generally unnecessary in cases of sustained hypertension where urinary catecholamines and metabolites are markedly elevated. For paroxysmal cases where episodes cannot be observed, glucagon stimulation testing may be considered. However, due to its low sensitivity and specificity as well as potential risks, pharmacological testing is typically not recommended.
Imaging Studies
Imaging studies are performed only after blood pressure is controlled using α-receptor antagonists. The following imaging modalities may be employed:
Ultrasound
This is useful for locating adrenal and extra-adrenal (e.g., cardiac) tumors. It has a high detection rate for adrenal tumors larger than 1 cm in diameter.
CT
More than 90% of tumors can be accurately localized using CT, which provides excellent spatial resolution for thoracic, abdominal, and pelvic tissues and may identify lung metastases. Due to tumor hemorrhage or necrosis, CT images often exhibit heterogeneous characteristics.
MRI
This is preferred for identifying paragangliomas in the skull base and neck, as well as metastatic tumors. MRI is also recommended for patients with metallic artifacts in CT imaging, children, pregnant women, or others requiring reduced radiation exposure.
Radioactive Iodine-131 Meta-iodobenzylguanidine (MIBG) Scintigraphy
MIBG is selectively concentrated in adrenergic vesicles, making it valuable for visualizing catecholamine-secreting tumors. It is particularly useful for detecting metastatic, recurrent, or extra-adrenal tumors as well as other neuroendocrine tumors.
Somatostatin Receptor Imaging
Pheochromocytomas and paragangliomas often express somatostatin receptors. Scintigraphy using radiolabeled somatostatin analogs such as octreotide facilitates localization and diagnosis.
18F-FDG PET-CT and 18F-DOPA PET-CT Imaging
These are useful for the localization and diagnosis of metastatic pheochromocytomas and paragangliomas.
This condition must be differentiated from centrally mediated sympathetic hyperactivity, which can also cause hypertension accompanied by elevated catecholamine levels in blood and urine. Symptoms such as palpitations, profuse sweating, anxiety, and increased cardiac output may similarly occur. Clonidine suppression testing can help differentiate whether catecholamines originate from sympathetic nerves or pheochromocytoma.
Treatment
Before surgical resection of pheochromocytoma, α-receptor antagonists are used to control blood pressure. If blood pressure remains inadequately controlled, calcium channel blockers may be added. β-receptor antagonists are only considered in patients with persistent tachycardia (heart rate >120 bpm) or supraventricular tachyarrhythmias, or in those with catecholamine-induced cardiomyopathy, and should only be administered after α-receptor antagonists have been used. The use of β-receptor antagonists prior to α-receptor antagonists can lead to acute heart failure. A minimum of 2 weeks of medication is required along with a normal or high-salt diet (except in patients with heart failure). Surgery is performed after achieving adequate control of blood pressure and heart rate and restoring blood volume.
The commonly used α-receptor antagonist is phenoxybenzamine, which has a long duration of action. It is initially administered orally at a dose of 10 mg twice daily, with gradual dose adjustments to achieve blood pressure control as needed. Side effects include nasal congestion due to nasal mucosal vasodilation, tachycardia, and orthostatic hypotension. Selective α-receptor antagonists, such as prazosin and doxazosin, may also provide effective blood pressure control while minimizing adverse effects associated with nonselective α-receptor blockade. Initial doses are kept low to avoid severe orthostatic hypotension. These drugs have shorter half-lives, allowing more flexible dose adjustments. Prazosin is initiated at 0.5 or 1 mg orally to assess patient sensitivity, with subsequent dose escalation as needed. Doxazosin is initiated at 2 mg once daily, and the dose can be gradually increased to a maximum of 32 mg per day as appropriate.
For hypertensive crises, emergency intervention is required. Phentolamine, at a dose of 1–5 mg, is administered by slow intravenous push while closely monitoring blood pressure. The drug is discontinued once blood pressure is reduced to approximately 160/100 mmHg, and treatment is followed by slow intravenous infusion of 10–15 mg of phentolamine dissolved in 500 ml of 5% glucose saline. Intravenous infusion of nitroprusside may also be used to reduce blood pressure.
Surgical resection of pheochromocytoma carries certain risks and must be performed under the management of skilled surgeons and anesthesiologists. During induction of anesthesia, throughout the surgery, and especially during manipulation of the tumor, sudden and severe increases in blood pressure and/or arrhythmias may occur. For sudden blood pressure spikes, rapid-acting α-receptor antagonists such as intravenous phentolamine or nitroprusside infusion are used. For arrhythmias, β2-receptor antagonists or other antiarrhythmic agents, such as lidocaine, may be employed. After tumor resection, if significant hypotension occurs, α-receptor antagonists should be discontinued immediately, and blood volume should be restored quickly to maintain normal central venous pressure. Vasopressive agents may be administered if required.
Catecholamine levels typically normalize within one week after pheochromocytoma resection. Blood pressure normalization occurs in approximately 75% of patients within one month, while 25% of patients may have persistent hypertension, although their blood pressure levels are generally lower than before surgery and respond well to standard antihypertensive medications. Since pheochromocytomas may present as multiple or recurrent tumors, postoperative follow-up and monitoring are necessary.
The treatment of malignant pheochromocytomas is challenging. These tumors generally show poor responsiveness to radiotherapy and chemotherapy. Symptomatic treatment with anti-adrenergic agents may be considered. Tyrosine hydroxylase inhibitors, such as α-methylparatyrosine, may be used to inhibit the biosynthesis of catecholamines. Treatment with radiolabeled iodine-131 MIBG (metaiodobenzylguanidine) has shown some efficacy, with reductions in blood pressure and catecholamine excretion after treatment. The prognosis of metastatic malignant pheochromocytomas is variable. Severe cases may lead to death within several months, while some patients may survive for over 10 years. The 5-year survival rate is approximately 45%. Common metastatic sites include bones, liver, lymph nodes, and lungs, followed by the brain, pleura, and kidneys.