| disease | Adrenal Medullary Hyperfunction |
The adrenal medulla is formed from sympathetic neuroblasts that migrate from the embryonic neural crest (ectoderm). These primitive sympathetic cells exhibit chromaffin properties. Sympathetic neuroblasts differentiate into two types of cells: ①sympathogonia: which mature into sympathetic ganglion cells, and ②chromaffinoblasts: which mature into chromaffin cells. Consequently, tumors arising from these cells can be classified into four types: sympathogonioma, sympathoblastoma, ganglioneuroma, and pheochromocytoma. Pheochromoblastoma, derived from chromaffinoblasts, is also known as malignant pheochromocytoma. Sympathogonioma and sympathoblastoma are often collectively referred to as neuroblastoma. Adrenal medullary tumors—pheochromocytoma—are the primary cause of medullary hyperfunction. Clinical cases have now confirmed that medullary hyperplasia can also lead to hyperfunction. Cases of pheochromocytoma were first reported over a century ago, but successful surgical removal of the tumor was not reported until 1927. In 1949, Holton, and in 1950, Goldenberg et al., discovered that pheochromocytomas secrete adrenaline and noradrenaline, which elucidated the clinical disease mechanism of pheochromocytoma. Previously, pheochromocytoma was considered a rare disease. In recent years, with continuous improvements in diagnostic methods, the number of detected cases has increased. Statistics indicate that its incidence accounts for 0.4–2.0% of all hypertension cases.
bubble_chart Etiology
The main causes of adrenal medullary hyperfunction include pheochromocytoma, malignant pheochromocytoma, and adrenal medullary hyperplasia.
Pheochromocytes are round or oval in shape, with a complete membrane and surrounded by abundant, engorged blood vessels. The tumors are generally large, with diameters ranging from 2 to 6 cm. Approximately 90% occur in the adrenal medulla, while the remaining 10% can occur in extra-adrenal locations. Extra-adrenal tumors are commonly found near the abdominal membrane, posterior to the main stirred pulse, including the organ of Zuckerkandl (Zuckerkandl's body). They may also be located near the kidneys, renal hilum, hepatic hilum, pancreatic head, spleen, abdominal stirred pulse, iliac vessels, ovaries, or bladder. Extra-abdominal pheochromocytomas are extremely rare, such as in the paravertebral region of the posterior mediastinum, and occasionally in the neck, intracranial cavity, or testes. About 90% of adrenal pheochromocytomas are solitary, while bilateral or multiple tumors account for 10%. The tumors are generally benign (approximately 90%), with a yellowish-orange cut surface, often showing hemorrhage, necrosis, and cystic changes, and are highly vascular. The stroma is sparse, and the tumor cells are large, irregularly polygonal, with abundant cytoplasmic granules resembling normal adrenal medullary cells but larger. Chromate can stain these granules, hence the name pheochromocytoma. Approximately 10% of pheochromocytomas are malignant, but it is sometimes difficult to distinguish them based solely on histomorphology. Malignancy is primarily indicated by invasive behavior, such as tumor membrane infiltration and metastasis to lymph nodes, liver, bones, lungs, and other organs.
In very rare cases, the clinical presentation and generation and transformation tests are consistent with a diagnosis of pheochromocytoma, but no tumor is found, which is due to adrenal medullary hyperplasia. The hyperplastic medullary cells are morphologically indistinguishable from normal medullary cells, except that the entire adrenal gland is enlarged, the gland is plump, the surface is raised, and the medullary layer is widened (with a cortex-to-medulla ratio greater than 1:10). Medullary hyperplasia is a bilateral sexually transmitted disease, but the degree of hyperplasia may differ between the two sides.The clinical manifestations are caused by the tumor cells secreting large amounts of Black Catechu phenolamines. Adrenal pheochromocytomas primarily secrete adrenaline, while extra-adrenal pheochromocytomas mainly secrete noradrenaline due to the lack of methyltransferase in the ectopic tumor tissue. The secretion of Black Catechu phenolamines by pheochromocytomas can be intermittent or continuous, leading to variable clinical symptoms.
Neuroblastomas and ganglioneuromas can also secrete Black Catechu phenolamines, presenting with clinical manifestations similar to those of pheochromocytoma.
In 1964, Pear collectively referred to cells widely present in endocrine glands and other tissues that can produce endocrine peptides and other substances as APUD cells (amine precursor uptake and decarboxylation cells). These cells all originate from the neural crest. Examples include pituitary cells secreting ACTH and melanocyte-stimulating hormone, pancreatic α, β, and δ cells secreting glucagon, insulin, and gastrin, gastrointestinal G cells secreting gastrin, thyroid C cells secreting calcitonin, adrenal medullary chromaffin cells, and bronchial cells secreting pulmonary vasoactive peptides in the lungs. When neural crest cells develop abnormally, multiple endocrine neoplasia (MEN) can occur. The resulting condition is called multiple endocrine neoplasia syndrome (MENS). Wermer proposed that this is a group of hereditary diseases characterized by autosomal dominant inheritance with high penetrance. Based on different clinical manifestations, it can be divided into: ① MEN type I (Wermer syndrome): including hyperparathyroidism, insulin-induced hypoglycemia, and gastrointestinal ulcers (Zollinger-Ellison syndrome). It may be accompanied by anterior pituitary or adrenal cortex hyperfunction. ② MEN type II (Sipple syndrome): further subdivided into type IIa (medullary thyroid carcinoma, pheochromocytoma) and type IIb (medullary thyroid carcinoma, hyperparathyroidism, pheochromocytoma, other multiple neuromas, mucosal neuromas, congenital megacolon). Some classify type II with multiple mucosal neuromas as MEN type III. Therefore, any pheochromocytoma accompanied by other endocrine disorders should raise suspicion of MENS type II. The medullary thyroid carcinoma in MEN type II originates from the C cells between thyroid follicles and can secrete large amounts of calcitonin, lowering blood calcium levels and thereby stimulating the parathyroid glands to cause parathyroid hyperplasia or adenoma. Thus, it is generally considered that the hyperparathyroidism is secondary. Occasionally, it may produce prostaglandins and ACTH, leading to diarrhea, steatorrhea, and cortisolism. The adrenal pheochromocytomas in MENS type II cases are mostly bilateral and have a malignant tendency. Therefore, such cases should prompt screening of other family members with blood relations, and patients should undergo long-term close follow-up.
bubble_chart Clinical Manifestations
Pheochromocytomas mostly occur in adults, typically between the ages of 20 and 50. Pediatric cases account for only 1/5 of the total. However, in children, 50% of cases may be bilateral, multifocal, or extra-adrenal. There is no significant gender difference. Familial pheochromocytomas are often multifocal, bilateral, or extra-adrenal and have a higher recurrence rate.
The clinical manifestations are all related to elevated secretion of Black Catechu phenols.
(1) Hypertension Clinically, persistent hypertension accounts for 2/3 of cases, while paroxysmal hypertension accounts for 1/3. Persistent hypertension includes cases where it is continuous from the onset or where paroxysmal exacerbations occur on a background of persistent hypertension. Some cases may initially present as paroxysmal hypertension and later become persistent. Early-stage hypertension is caused by Black Catechu phenols secreted by the tumor, while late-stage [third-stage] hypertension results from secondary lesions in the heart, blood vessels, and kidneys due to prolonged and recurrent hypertension.
The clinical presentation of paroxysmal hypertension can be highly characteristic. Sudden onset of palpitations, shortness of breath, chest tightness, dizziness, headache, and sweating may occur, sometimes accompanied by nausea, vomiting, abdominal pain, blurred vision, and other symptoms. Patients may appear tense, anxious, or fearful, with pallor, limb tremors, and a sudden rise in blood pressure to above 26.7 kPa (200 mmHg), or even exceeding 40.0 kPa (300 mmHg). Hypertensive episodes may be accompanied by tachycardia, bradycardia, or arrhythmias. Occasionally, cerebral hemorrhage, hypertensive encephalopathy, left heart failure, pulmonary edema, unconsciousness, and spasms may occur. Episodes typically last for several tens of minutes but can persist for hours or even tens of hours. After the episode subsides, patients often experience extreme fatigue, weakness, flushing of the complexion and skin, profuse sweating, salivation, constricted pupils, and increased urine output. Episodes are often triggered by vigorous exercise, changes in posture, abdominal pressure, hunger, or emotional stress. Pheochromocytomas located around the bladder or rectum may be triggered by bladder filling, urination, or defecation. In the early stages, episodes are milder and less frequent, occurring perhaps once every few months, but they gradually increase in frequency and may even occur multiple times a day.
Pheochromocytomas can also cause hypotension and shock. Hypotension often follows a hypertensive episode, but it may also occur without significant hypertension. The causes of hypotension include: ① Prolonged and excessive stimulation by Black Catechu phenols leads to sustained vasoconstriction, resulting in tissue hypoxia, increased capillary permeability, and reduced plasma volume. Alternatively, sudden cessation of Black Catechu phenol secretion after massive release may cause vasodilation, leading to a sharp increase in vascular capacity and insufficient effective blood volume, resulting in shock. ② β-receptor stimulation by epinephrine causes vasodilation. ③ Heart failure and arrhythmias reduce cardiac output.
In some cases, prolonged hypertension (which may be asymptomatic) can lead to retinal hemorrhage, exudation, and vascular sclerosis, resulting in decreased vision.
(2) Metabolic changes These include increased basal metabolic rate and decreased glucose tolerance. Patients may exhibit fever, weight loss, and symptoms resembling hyperthyroidism. Due to increased glycogenolysis and suppressed insulin secretion, fasting blood glucose levels rise, and glucose tolerance tests show diabetic-like curves, sometimes even with glycosuria. During hypertensive episodes, blood sugar may rise significantly. Some cases may present with high fever, raising suspicion of infection, possibly due to increased metabolic rate and tumor tissue necrosis.
(3) Abdominal Mass Large tumors can be palpated in the abdomen, but this accounts for only a minority of cases. Compression of the tumor may induce symptoms such as hypertension. However, large tumors do not necessarily correspond to severe symptoms. Due to factors like necrosis and cystic degeneration, the functional activity of the tumor is often low, leading to less obvious symptoms, which can result in misdiagnosis as other tumors.
(4) A small number of pheochromocytoma cases may present no clinical symptoms and are only discovered when the tumor gradually enlarges and causes local compression symptoms. The reasons may include: ① The tumor's endocrine function is not prominent. ② The body has compensatory mechanisms, such as dopamine counteracting the vasodilatory effects of adrenaline and noradrenaline. ③ The tumor's secretory function is intermittent. The latter two scenarios must be taken seriously, as performing surgery to remove the tumor without adequate preoperative preparation may lead to sudden secretion of large amounts of catecholamines due to anesthesia or surgical stimulation, resulting in hypertensive crisis, shock, or even death. Surgery for undiagnosed pheochromocytoma is one of the causes of sudden death in patients undergoing retroperitoneal tumor surgery.
Some cases may exhibit hypertension symptoms, but patients remain unaware until the condition is detected during physical examination or vision impairment checks.
If there are typical episodes of hypertension and the tumor can be palpated, the diagnosis is relatively easier, but special diagnostic methods are still required to confirm it. However, because pheochromocytomas often present with atypical and variable symptoms clinically, leading to misdiagnosis in some cases, all hypertensive patients should be tested for the excretion of Black Catechu phenols and their major metabolites in urine. At the same time, the possibility of pheochromocytoma should also be considered for abdominal masses of unknown origin.
(1) Measurement of Black Catechu phenols and their metabolites in blood and urine: Certain foods and medications can interfere with the measurement, so they must be discontinued before testing (Table 1).
| Item | Increase | Decrease |
| Black Catechu phenols | coffee bean, banana, methyldopa, quinine, theophylline, chloral hydrate, isoproterenol; if fluorescence method is used, tetracycline, erythromycin, and oxytetracycline cannot be used | clonidine |
| VMA | coffee bean, chocolate, citrus fruits, aspirin, sulfonamides, penicillin, levodopa, nitroglycerin, nalidixic acid | clofibrate (atromid-S) |
| MN | chlorpromazine |
During hypertensive episodes, the increase in Black Catechu phenols in plasma or urine is more pronounced, especially when measuring the excretion of Black Catechu phenols and vanillylmandelic acid (VMA) in the 3-hour urine after an episode and comparing it with the 3-hour excretion during non-episodic periods.
The normal 24-hour urinary excretion of VMA is 1–6 mg. A level exceeding 10 mg/24h is diagnostically significant. For patients with seasonal disease who have difficulty collecting 24-hour urine, the ratio of VMA to creatinine in urine can also be measured. The normal range is 0.25–3.5 μg/mg, with a normal average of 1.4 μg/mg. The normal 24-hour urinary excretion of Black Catechu phenols is 10–30 μg for adrenaline and 20–60 μg for noradrenaline.
The normal plasma levels of Black Catechu phenols are <1 μg/L, with adrenaline at 0.05±0.03 μg/L and noradrenaline at 0.2±0.08 μg/L.
(2) Pharmacological tests: These are only used when the diagnosis is uncertain. If the diagnosis is already confirmed, these tests are not performed due to their potential risks and side effects. Preparations before testing include: ① Discontinue sedatives and all foods and medications that interfere with Black Catechu phenol measurement for 2 days. ② Rest supine for 15 minutes and repeat blood pressure measurements until it stabilizes at a certain level. ③ Empty the bladder before the test. ④ Prepare noradrenaline, phentolamine (rigitine), and other emergency medications.
1. Provocative Tests Applicable for cases with unclear hypertension and systolic blood pressure below 22.7 kPa (170 mmHg). ① Tuina test: Perform tuina on the mass or the suspected site of pheochromocytoma while monitoring blood pressure changes. ② Cold pressor test: Measure blood pressure in the right arm while immersing the left hand in 4°C cold water up to the wrist for 1 minute. Record blood pressure at 15 seconds, 30 seconds, 60 seconds, 2 minutes, 5 minutes, and 15 minutes until blood pressure returns to normal. A positive result is indicated if blood pressure rises by more than 4.6/3.33 kPa (35/25 mmHg) from baseline. ③ Histamine test: Rapidly inject 0.05 mg of histamine intravenously, then measure blood pressure every 30 seconds for 3 minutes, followed by every 2 minutes for 15 minutes until blood pressure stabilizes. A positive result is indicated if blood pressure exceeds baseline by 6/3.33 kPa (45/25 mmHg) and persists for 5 minutes, suggesting possible pheochromocytoma. Measuring urinary VMA excretion (1-hour, 3-hour, or 24-hour) after the provocative test and comparing it with pre-test levels provides greater significance. If a hypertensive crisis occurs during the test, intravenous phentolamine (Rigitine) can be administered as an antagonist. The histamine test has a false-positive rate of approximately 10% and a false-negative rate of over 5%. Side effects include headache, facial flushing, tachycardia, hypotension, and bronchospasm. It is contraindicated in patients with asthma. ④ Glucagon test: The dose is 0.5–1.0 mg, and the method is the same as the histamine test. ⑤ Tyrosine test: The dose is 1 mg, and the method is the same as the histamine test.
2. Suppression Test The preparation before the test is the same as for the provocation test. It is suitable for patients with blood pressure higher than 24/14.66 kPa (180/110 mmHg). ① Phentolamine (Rigitine): After rapid intravenous injection of 5 mg phentolamine (diluted with 5 ml of normal saline), a positive result is indicated if blood pressure drops by more than 4.6/3.33 kPa (35/25 mmHg) and lasts for 3–5 minutes, suggesting the possibility of pheochromocytoma. If shock occurs, norepinephrine can be used as an antagonist. ② Phenoxybenzamine (Dibenzyline) Test: Oral administration of phenoxybenzamine 20 mg 3–4 times a day for 2 weeks. A positive result is indicated by a drop in blood pressure, reduced episodes, and significant improvement in symptoms. This also serves as one of the preoperative preparations.
(3) Tumor Localization The localization methods for pheochromocytoma are the same as for other adrenal tumors, such as B-ultrasound and CT, which are commonly used diagnostic methods. Pheochromocytomas are generally large in size and rich in blood supply, making them relatively easy to detect. However, before performing certain invasive examinations (e.g., adrenal angiography), thorough preparation should be made, as with surgery, to prevent hypertensive crises and accidents during the examination. Adrenal stirred pulse angiography or abdominal aortic stirred pulse angiography often reveals a highly vascularized tumor. Thick supplying stirred pulses are frequently visible. Due to the tumor's rich blood supply, abdominal aortic stirred pulse angiography may sometimes not only display larger pheochromocytomas in the adrenal region but also ectopic or multiple other pheochromocytomas. This is highly beneficial for surgery. In addition to visualizing the tumor, adrenal venography can also help diagnose by measuring the Black Catechu phenolamine content in venous blood samples taken from different sites via a venous catheter. Nuclear scanning using radionuclide-labeled adrenal medullary imaging agents (such as 131I-MIBG) also aids in tumor localization.
bubble_chart Treatment Measures
Surgical removal of the tumor is the best treatment method. For patients with severe complications who cannot tolerate surgery or those with malignant tumors that have metastasized, drug therapy can be used.
(1) Surgical Treatment
1. Preoperative preparation ① Application of adrenergic receptor blockers. Phenoxybenzamine should be administered orally before surgery, starting with a dose of 10mg twice daily and gradually increasing to 20mg three to four times daily. This should be continued for at least two weeks until blood pressure is normalized and symptoms are largely controlled. Side effects include stuffy nose and orthostatic collapse. For cases with excessive heart rate, propranolol can be administered orally to control the heart rate below 90 beats per minute. ② Blood volume replenishment. After surgical removal of the tumor, the plasma levels of Black Catechu phenols drop sharply, leading to reduced vascular tension and dilation of small blood vessels, resulting in relative blood volume insufficiency, which can exacerbate intraoperative shock. Therefore, blood volume should be adequately replenished before surgery. Whole blood or medium molecular weight dextran solution can be transfused. Sufficient blood supply should also be prepared for intraoperative use.
2. Anesthesia preparation ① Atropine should not be used for preoperative anesthesia; instead, scopolamine 0.3mg can be administered intramuscularly. ② Prepare one intravenous infusion channel exclusively for blood transfusion and another for administering drugs to regulate blood pressure and arrhythmias. If a large right adrenal tumor may require blocking the inferior vena cava during surgery, upper limb or jugular vein infusion should be chosen. Norepinephrine and phentolamine are primarily used to regulate blood pressure. The most significant blood pressure fluctuations occur during tumor separation and removal, requiring close monitoring. At least one intravenous infusion channel should remain open after surgery. Some patients may still require intravenous norepinephrine to maintain blood pressure for a period before gradual withdrawal. ③ Most cases can undergo surgery under continuous epidural anesthesia. If a combined thoracoabdominal incision is needed, general anesthesia can be selected.
3. Selection of surgical incision For adrenal pheochromocytomas that can be preoperatively localized, an 11th intercostal incision or lumbar incision can be used. If localization is unclear, there are multiple or ectopic pheochromocytomas in the abdominal cavity, or in cases of adrenal medullary hyperplasia, an abdominal incision can be used for exploration. For large adrenal pheochromocytomas compressing the inferior vena cava, a combined thoracoabdominal incision through the 8th intercostal space can be chosen. During surgery, the inferior vena cava above and below the tumor should be freed first before tumor removal for safety.
4. Intraoperative exploration Some ectopic and multiple pheochromocytomas are diagnosed preoperatively, but others require intraoperative exploration. During exploration, if a mass is palpated and squeezed, blood pressure will rise significantly if it is a pheochromocytoma. However, this may not be obvious in cases prepared with excessive phenoxybenzamine. Tumor separation should be gentle to avoid blood pressure fluctuations due to squeezing. The anesthesiologist should be notified when ligating the tumor's blood supply or removing the tumor to prepare for possible sudden blood pressure drops. If blood pressure does not drop or drops only slightly after tumor removal, with systolic pressure remaining above normal or quickly returning to its original level, there may be residual undetected tumors, and further exploration is needed. Over 98% of ectopic pheochromocytomas are located between the abdominal and pelvic cavities, so the abdominal membrane can be opened for exploration, especially around the adrenal glands and near major blood vessels.
During any abdominal mass surgery, if significant blood pressure fluctuations occur, the possibility of pheochromocytoma should be considered, and emergency measures should be organized immediately. If necessary, surgery should be halted, and after a clear diagnosis, proper preparation should be made before proceeding with tumor removal.
For cases where the tumor is too large to remove, some authors report partial tumor enucleation under the membrane, achieving certain effects.
For cases of bilateral adrenal medullary hyperplasia, total adrenalectomy can be performed on the more significantly hyperplastic side. If blood pressure does not drop postoperatively, two-thirds of the contralateral side can be removed. The medulla can be scraped or treated with formaldehyde during surgery. Preoperative preparation is similar to that for pheochromocytoma, and the possibility of adrenal cortical insufficiency should be noted.
5. Postoperative Management In some cases, blood pressure may remain unstable after tumor removal, requiring adjustment of the intravenous drip rate of norepinephrine or phentolamine to achieve balance. Such cases should be closely monitored for blood pressure changes postoperatively to regulate the concentration and drip rate of medication until the condition stabilizes, after which the dosage can be gradually reduced. Most patients can discontinue medication within 1 to 2 days after surgery.
Some cases of postoperative hypertension are caused by secondary renal or cardiovascular diseases, requiring further examination and treatment.
Due to the possibility of tumor recurrence or regeneration, patients should undergo long-term follow-up. If recurrence or metastasis occurs, the possibility of acute tumors should be considered.
(2) Drug Therapy
Commonly used adrenergic receptor blockers include α-receptor blockers such as phenoxybenzamine and β-receptor blockers such as propranolol. These are generally used as preoperative preparations. Some patients with severe complications or unresectable large tumors may take them long-term to control symptoms. Some authors have reported attempting treatment with high-dose radionuclide-labeled adrenal medullary cholesterol.
α-Methyl-para-tyrosine can competitively inhibit tyrosine hydroxylase, blocking the synthesis of dopamine from tyrosine, thereby inhibiting the synthesis of catecholamines, and may also be tried. The dose is 600–1200 mg/d, taken orally in divided doses. Side effects include drowsiness, anxiety, dry mouth, milk regurgitation, tremor, and paralysis.
