| disease | Pheochromocytoma (Surgery) |
Pheochromocytomas originate from chromaffin cells. During the embryonic period, the distribution of chromaffin cells is related to the sympathetic ganglia of the body. 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 occur anywhere from the carotid body to the pelvic region, 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 Pathological Changes
More than 90% of pheochromocytomas are benign tumors. The tumor appears brownish-yellow on section, with rich blood vessels, minimal stroma, and frequent hemorrhage. The tumor cells are large, irregularly polygonal, with abundant granules in the cytoplasm; the cells can be stained by chromium salts, hence the name pheochromocytoma. According to statistics, 80–90% of pheochromocytomas occur in the chromaffin cells of the adrenal medulla, of which about 90% are unilateral and single lesions. Multiple tumors, including those occurring bilaterally in the adrenal glands, account for approximately 10%. Pheochromocytomas originating outside the adrenal glands account for about 10%; domestic statistical results are slightly higher in this regard. Malignant pheochromocytomas constitute about 5–10% and can metastasize to lymph nodes, liver, bones, lungs, etc. A small number of pheochromocytomas may coexist with multiple subcutaneous neurofibromas, of which approximately 25% are linked to Hippel-Lindau syndrome. Pheochromocytoma is also a major manifestation of type II multiple endocrine neoplasia (MEN II). MEN II has a familial incidence and is inherited in an autosomal dominant manner, 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 α and β 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 more common in young and middle-aged adults, with a peak incidence between the ages of 30 and 50, and shows 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 blood pressure can exceed 26.6 kPa (200 mmHg), and diastolic pressure also increases markedly. During an episode, symptoms may include palpitation, shortness of breath, chest tightness, headache, pale complexion, profuse sweating, and blurred vision. In severe cases, hypertensive crises such as cerebral hemorrhage or pulmonary edema may occur. After the episode subsides, patients often experience extreme fatigue and weakness, and may exhibit facial flushing. Attacks 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 positively correlated with tumor size.
Some patients may present with sustained hypertension. It is 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, possibly due to tumor necrosis, intratumoral hemorrhage leading to sudden cessation of catecholamine release, or severe cardiac complications. Such cases often have a poor prognosis.
2. Metabolic disturbances: Catecholamines stimulate pancreatic α-receptors, reducing insulin secretion. They act on hepatic α- and β-receptors and muscle β-receptors, increasing gluconeogenesis and glycogenolysis while decreasing peripheral glucose utilization, resulting in hyperglycemia or impaired glucose tolerance. Catecholamines also enhance the secretion of pituitary TSH and ACTH, increasing thyroid hormone and adrenal corticosteroid levels, which elevates basal metabolic rate, raises blood sugar, accelerates fat breakdown, and leads to weight loss. A few patients may develop hypokalemia.
3. Other manifestations: Catecholamines relax gastrointestinal smooth muscles, weakening peristalsis and causing constipation, which can sometimes be intractable. Severe contraction spasms of gastrointestinal small arteries may lead to mucosal ischemia and, rarely, necrosis or perforation. Due to tumor growth compressing adjacent organs, corresponding clinical symptoms may arise.
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 episodes, and a portion of cases are malignant pheochromocytomas, early diagnosis and treatment are essential. However, due to the intermittent nature of symptoms in many patients, certain tests and examinations can be challenging, necessitating a comprehensive approach in selecting diagnostic methods.
1. Laboratory Tests General 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 the specific diagnostic test.
During metabolism, epinephrine and norepinephrine are first degraded into metanephrines and ultimately into 3-methoxy-4-hydroxymandelic acid (VMA). Therefore, laboratory tests 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 testing outside an attack phase can impact accuracy. These factors must be carefully considered.
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 dominated by epinephrine secretion.
In recent years, sensitive and specific radioenzymatic assays have enabled the separate measurement of plasma norepinephrine, epinephrine, and dopamine. Although these tests demand stringent laboratory conditions and are costly, they currently represent the most sensitive diagnostic method for pheochromocytoma. Notably, this approach can detect pheochromocytoma even in normotensive individuals.
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. Traditional laboratory tests only measure free catecholamines. Subsequent studies have explored the measurement of bound catecholamines.
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 categories: - **Alpha-adrenergic receptor blockers**, such as phentolamine (Regitine), are used for patients with sustained hypertension or during hypertensive episodes. If hypertension is caused by excessive norepinephrine and epinephrine secretion, intravenous phentolamine will rapidly lower blood pressure within 2 minutes. A positive result is defined as a systolic blood pressure drop >4.65 kPa (35 mmHg) and a diastolic drop >3.3 kPa (25 mmHg), sustained for 3-5 minutes. Sedatives and antihypertensive medications should be discontinued for one week before testing to ensure accuracy.
Reports suggest the use of clonidine suppression tests. After oral clonidine administration, plasma catecholamines in non-pheochromocytoma hypertensive patients are suppressed and decrease. In contrast, the autonomous catecholamine secretion by pheochromocytoma tumors remains unaffected, leaving plasma catecholamine levels unchanged.
The provocation test involves inducing an episode in patients with paroxysmal hypertension using histamine or similar agents when they are not experiencing an attack and their blood pressure is normal. A positive result is indicated if, within 2 minutes of intravenous histamine injection, the systolic blood pressure rises 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 those with primary hypertension, blood pressure may decrease after the injection, accompanied by symptoms such as facial flushing, headache, and nausea. This test carries certain risks, and preparations should be made to have phentolamine on hand in case of excessive blood pressure elevation. The test is contraindicated in individuals with a history of myocardial infarction, cerebral hemorrhage, or heart failure.
Glucagon can stimulate the release of catecholamines from adrenal medullary pheochromocytoma, causing hypertension, but this reaction does not occur in 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 factors such as tumor 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 tumors that could not be localized by other methods. It can provide useful reference data for CT scans.
In recent years, the development of 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 removal of pheochromocytoma is the most effective treatment, but the procedure 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 major blood vessels, which may lead to massive bleeding. Therefore, proper management before, during, and after surgery is critically important.
In patients with pheochromocytoma, the excessive secretion of catecholamines causes prolonged vasoconstriction, resulting in high blood pressure but often insufficient blood volume. Thus, preoperative preparation with adequate medication is essential to achieve vasodilation, lower blood pressure, and expand blood volume. Currently, the alpha-adrenergic receptor blocker phenoxybenzamine is commonly used, with a dose of 10–20 mg, 2–3 times daily for 2–6 weeks. The beta-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 drugs should meet the following conditions: ① no significant inhibition of cardiac pump function; ② no increase in sympathetic excitability; ③ intraoperative blood pressure control; and ④ facilitation of blood volume restoration and blood pressure maintenance after tumor removal. General anesthesia remains the preferred approach. The surgical incision depends on the accuracy of diagnosis and localization as well as the tumor size, with exploratory laparotomy often being the safer option.
The preoperative placement of a Swan-Ganz catheter to monitor pulmonary capillary wedge pressure can accurately and reliably assess the patient's cardiac pumping status and effectively maintain blood volume, providing favorable conditions for the successful completion of the surgery.
Alpha-methyltyrosine inhibits catecholamine synthesis and can be used in combination with phenoxybenzamine for patients who are not candidates for surgery, though long-term use may lead to drug resistance.
