bubble_chart Overview

Pheochromocytoma originates from chromaffin cells. During the embryonic stage, the distribution of chromaffin cells is associated with the body's sympathetic ganglia. As the fetus develops and matures, the majority of chromaffin cells degenerate, with the remaining portions forming the adrenal medulla. Therefore, most pheochromocytomas occur in the adrenal medulla. Extra-adrenal pheochromocytomas can arise anywhere from the neck to the pelvis but are primarily found in the paravertebral sympathetic ganglia (mainly in the posterior mediastinum) and near the bifurcation of the abdominal aorta (the organ of Zuckerkandl).

bubble_chart Etiology

More than 90% of pheochromocytomas are benign tumors. The tumor appears brownish-yellow on cut section, with abundant blood vessels, minimal stroma, and frequent hemorrhage. The tumor cells are large, irregularly polygonal, with abundant cytoplasmic granules; the cells can be stained by chromium salts, hence the name pheochromocytoma. According to statistics, 80–90% of pheochromocytomas arise from chromaffin cells in the adrenal medulla, of which about 90% are unilateral and solitary. Multiple tumors, including those occurring bilaterally in the adrenal glands, account for approximately 10%. Extra-adrenal pheochromocytomas constitute about 10%; domestic statistical results are slightly higher. Malignant pheochromocytomas account for 5–10% and can metastasize to lymph nodes, liver, bones, lungs, etc. A small number of pheochromocytomas may coexist with multiple subcutaneous neurofibromas, about 25% of which are linked to Hippel-Lindau syndrome. Pheochromocytoma is also a major manifestation of multiple endocrine neoplasia type II (MEN II). MEN II has a familial inheritance pattern and is autosomal dominant, accounting for about 5–10% of pheochromocytoma cases; patients with bilateral adrenal pheochromocytomas should be particularly alert to the possibility of MEN II.

Pheochromocytomas can autonomously secrete catecholamines, including epinephrine, norepinephrine, and dopamine. Epinephrine and norepinephrine act on adrenergic receptors, such as alpha and beta receptors, affecting corresponding tissues and organs and causing a series of clinical manifestations. All pathophysiological bases in patients with pheochromocytoma are directly related to this secretory function of the tumor.

bubble_chart Clinical Manifestations

Pheochromocytoma is most common in young and middle-aged adults, with the peak incidence occurring between the ages of 30 and 50, and there is no significant difference between genders.

1. Cardiovascular manifestations: Due to the intermittent release of large amounts of catecholamines into the bloodstream, vasoconstriction occurs, peripheral resistance increases, heart rate accelerates, and cardiac output rises, leading to paroxysmal surges in blood pressure. Systolic pressure can exceed 26.6 kPa (200 mmHg), and diastolic pressure also increases significantly. During an episode, patients may experience palpitations, shortness of breath, chest tightness, headache, pale complexion, profuse sweating, blurred vision, and in severe cases, cerebral hemorrhage or pulmonary edema as part of a hypertensive crisis. After the episode subsides, patients often feel extremely fatigued and weak, and may exhibit facial flushing. Episodes can be triggered by sudden changes in posture, emotional stress, vigorous exercise, coughing, or bowel movements. The frequency and duration of episodes vary widely among individuals and are not necessarily correlated with tumor size.
   Some patients may present with sustained hypertension. It has been reported that approximately 90% of pediatric patients exhibit sustained hypertension, while about 50% of adults do as well. The difference lies in the manifestations of excessive adrenaline or noradrenaline secretion. A small number of patients may experience episodic hypotension or shock, which may be related to tumor necrosis, intratumoral hemorrhage leading to sudden cessation of catecholamine release, or severe cardiac events. The prognosis in such cases is often poor.
   In 1958, Szakas introduced the concept of catecholamine cardiomyopathy, characterized by direct toxic effects of catecholamines on the myocardium, leading to myocardial hypertrophy, edema, focal hemorrhage, endocardial thickening, and inflammatory cell infiltration. The clinical presentation resembles myocarditis, and severe cases may develop heart failure or life-threatening arrhythmias.
2. Metabolic disturbances: Catecholamines stimulate pancreatic alpha receptors, reducing insulin secretion, and act on hepatic alpha and beta receptors as well as muscle beta receptors, increasing gluconeogenesis and glycogenolysis while decreasing peripheral glucose utilization, resulting in hyperglycemia or impaired glucose tolerance. Catecholamines also promote increased secretion of TSH and ACTH from the pituitary, leading to elevated thyroid hormone and adrenal cortical hormone levels, which raise the basal metabolic rate, increase blood sugar, and accelerate fat breakdown, causing weight loss. A small number of patients may develop hypokalemia.
3. Other manifestations: Catecholamines relax gastrointestinal smooth muscle, weakening peristalsis and potentially causing constipation, which can sometimes be severe. Severe contraction spasms of gastrointestinal small vessels may lead to ischemia of the gastrointestinal mucosa, occasionally resulting in necrosis or perforation. Due to tumor growth compressing adjacent organs, corresponding clinical symptoms may arise.

bubble_chart Diagnosis

Pheochromocytoma accounts for approximately 0.5-1% of the causes of hypertension. Over 90% of patients can be cured through surgery. Because this condition carries the risk of triggering emergency incidents during attacks, and some cases may involve malignant pheochromocytomas, early diagnosis and treatment are essential. However, due to the intermittent nature of the attacks, certain laboratory tests and examinations can be challenging, so the choice of diagnostic methods should be carefully considered.

1. Laboratory Tests Routine laboratory tests lack specificity. Decreased glucose tolerance, elevated basal metabolic rate, and serum protein-bound iodine levels may provide some reference value. Typically, the measurement of blood and urine catecholamines and their metabolites serves as a specific diagnostic tool.

During metabolism, epinephrine and norepinephrine are first degraded into metanephrines and ultimately into 3-methoxy-4-hydroxymandelic acid (VMA). Therefore, laboratory tests often measure urinary metanephrines and VMA as diagnostic indicators for functional pheochromocytoma. However, metanephrines and VMA can be affected by certain medications (e.g., monoamine oxidase inhibitors, chlorpromazine, lithium preparations) and foods (e.g., coffee beans, bananas), which may interfere with test results. Additionally, incomplete urine collection or whether the sample is taken during an attack can influence the outcome. These factors should be given sufficient attention.

Urinary catecholamine measurement is more sensitive and reliable but requires higher technical expertise. It is considered the most sensitive indicator of short-term catecholamine secretion and holds greater diagnostic value for cases where epinephrine secretion predominates.

In recent years, sensitive and specific radioenzymatic assays have been developed to measure plasma norepinephrine, epinephrine, and dopamine individually. Although these tests demand high experimental conditions and are costly, they are currently the most sensitive methods for diagnosing pheochromocytoma, particularly for detecting normotensive cases.

In recent years, Kuchel et al. discovered that the three components of catecholamines—norepinephrine, epinephrine, and dopamine—exist in the bloodstream in two forms: free and bound. In peripheral circulation, 80% of norepinephrine and epinephrine are in the bound state, while nearly 100% of dopamine is bound. Previous laboratory tests only measured free catecholamines. Subsequent measurements of bound catecholamines revealed...

2. Pharmacological Tests Pharmacological tests lack strong specificity and may yield false negatives, false positives, and side effects. However, they hold diagnostic value for clinically suspected cases where catecholamine measurements show no abnormalities.

Pharmacological tests fall into two main categories: - **Alpha-adrenergic receptor blockers**, such as phentolamine (Regitine), are used for patients with sustained hypertension or during hypertensive episodes. If elevated blood pressure is due to excessive norepinephrine and epinephrine secretion, intravenous phentolamine will cause a rapid drop in blood pressure within 2 minutes. A positive result is defined as a systolic blood pressure decrease of >4.65 kPa (35 mmHg) and a diastolic decrease of >3.3 kPa (25 mmHg), lasting 3–5 minutes or longer. Sedatives and antihypertensive medications should be discontinued for one week before the test to ensure accuracy.

Some reports suggest using clonidine for suppression testing. After oral administration, non-pheochromocytoma hypertensive patients show suppressed plasma catecholamine levels, whereas pheochromocytoma patients exhibit autonomous catecholamine secretion that remains unaffected, leaving plasma catecholamine levels unchanged.

The provocation test is performed by using histamine and other agents to induce an episode in patients with paroxysmal hypertension when they are not experiencing an attack and their blood pressure is not elevated. A positive result is indicated if, within 2 minutes after intravenous injection of histamine, the systolic blood pressure increases by more than 6.65 kPa (50 mmHg) and the diastolic blood pressure increases by more than 3.99 kPa (30 mmHg). In normal individuals and patients with essential hypertension, blood pressure may decrease after drug administration, accompanied by facial flushing, headache, nausea, etc. This test carries certain risks, and preparations such as phentolamine should be readily available during the procedure. The test is contraindicated in individuals with a history of myocardial infarction, cerebral hemorrhage, or heart failure.

Glucagon can stimulate the release of Black Catechu phenols from adrenal medullary pheochromocytoma, causing hypertension, but it does not have this effect on normal individuals or patients with primary hypertension. Its side effects are much milder than those of histamine, making it safer.

3. Localization Diagnosis B-mode ultrasound and CT scans have high diagnostic accuracy for pheochromocytoma and are non-invasive, making them the preferred examination methods when available. Tumors larger than 1.5 cm can be accurately localized via CT scans, while those smaller than 1 cm are more challenging and require comprehensive analysis with other tests. In addition to localizing and measuring the tumor, CT scans can also assess whether the tumor has infiltrated or metastasized based on its boundaries, aiding in the selection of appropriate treatment methods.

Segmental venous blood sampling for localization is highly valuable in locating pheochromocytomas, especially for small tumors, ectopic tumors, or cases where other examinations fail to localize the tumor. It can provide useful references for CT scans.

In recent years, 131I-metaiodobenzylguanidine (131I-MIBG) imaging has provided an important method for the diagnosis and localization of pheochromocytoma. The principle is that MIBG is chemically similar to norepinephrine and can be taken up by the adrenal medulla and pheochromocytoma. Therefore, it is specific for pheochromocytoma detection and can differentiate whether tumors in the adrenal gland or other locations are pheochromocytomas. This method is safe, specific, and highly accurate.

bubble_chart Treatment Measures

Surgical resection of pheochromocytoma is the most effective treatment, but the surgery carries certain risks. Compression of the tumor during anesthesia and surgery can easily cause blood pressure fluctuations; the tumor is highly vascularized and adjacent to large blood vessels, which may lead to massive bleeding. Therefore, proper preoperative, intraoperative, and postoperative management is extremely important.

In patients with pheochromocytoma, the excessive secretion of catecholamines causes long-term vasoconstriction, resulting in high blood pressure but often insufficient blood volume. Therefore, preoperative preparation with an adequate course of medication is necessary to achieve vasodilation, lower blood pressure, and expand blood volume. Currently, the α-adrenergic receptor blocker phenoxybenzamine is commonly used, with a dose of 10–20 mg, 2–3 times daily for 2–6 weeks. The β-adrenergic receptor blocker propranolol, 10 mg, 2–3 times daily for about 1 week before surgery, can prevent intraoperative tachycardia and arrhythmias.

The choice of anesthesia method and anesthetic drugs should meet the following conditions: (1) no significant inhibition of cardiac pump function; (2) no increase in sympathetic excitability; (3) effective intraoperative blood pressure control; (4) facilitation of blood volume restoration and blood pressure maintenance after tumor resection. General anesthesia remains the preferred approach. The surgical incision depends on the accuracy of diagnosis and localization as well as the size of the tumor, with exploratory abdominal incisions being more reliable in most cases.

The preoperative placement of a Swan-Ganz catheter to monitor pulmonary capillary wedge pressure can accurately and reliably assess the patient's cardiac pump function and effectively maintain blood volume, providing favorable conditions for the successful completion of the surgery.

α-Methyltyrosine can inhibit the synthesis of catecholamines and may be used in combination with phenoxybenzamine for patients who are not candidates for surgery, but long-term use may lead to drug resistance.