BACKGROUND: A pheochromocytoma is a rare cause of secondary hypertension. Its diagnosis is important as the hypertension is usually curable by resection of the tumor, whereas the condition is potentially lethal if undetected. Biochemical confirmation of excessive catecholamine production is a prerequisite to a definitive diagnosis. Various studies from other countries have indicated that measuring of the urinary metanephrine, using a specific procedure, is the single most reliable screening test for all patients suspected of having a pheochromocytoma. However, the diagnostic value of urinary metanephrine has never been reported in Korea. We investigated the diagnostic value of 24-hours urinary metanephrine in patients with a suspected pheochromocytoma. METHODS: This was a retrospective evaluation study, which included 95 patients with sustained hypertension and paroxysmal symptoms, and 38 patients with asymptomatic adrenal incidentaloma at Seoul National University Hospital, between July 2000 and October 2002. We performed the 24- hour urinary total metanephrine test on all patients. The diagnosis of a pheochromocytoma was applied only when confirmed by pathological analysis of a resected specimen. The possibility of a pheochromocytoma was ruled out when all biochemical tests were normal, which were performed at least in duplicate, or there was no evidence of a mass in abdominal radiological studies or histological verification. We determined the upper reference limit for urinary metanephrine as 1.3mg/day and calculated the sensitivity and specificity of the 24-hour urinary metanephrine test. RESULTS: Seventeen patients were diagnosed with a pheochromocytoma. The total metanephrine measurement had sensitivities and specificities of 82.4 and 73.3% in all the patients, 90.9 and 66.7% in patients with hypertension and paroxysmal symptoms, and 66.7 and 90.6% in patients with adrenal incidentaloma, respectively. CONCLUSION: The urinary total metanephrine measurement had relatively lower sensitivities and specificities than in other countries(sensitivity: 83~100%, specificity: 80~98%). The sensitivity of urinary metanephrine was relatively high in patients with hypertension and paroxysmal symptoms, and the specificity was high in patients with an adrenal incidentaloma. We suggest that normetanephrine and metanephrine should be separately measured, and a reasonable upper reference limit be used. It may also be necessary to measure urinary metanephrine together with urinary catecholamine or VMA to improve the diagnostic value of the urinary metanephrine test.
Diagnosis ; Humans ; Hypertension ; Korea ; Mass Screening* ; Metanephrine* ; Normetanephrine ; Pheochromocytoma* ; Retrospective Studies ; Sensitivity and Specificity ; Seoul

High-resolution imaging techniques have increased the detection rate of adrenal incidentaloma. We developed a method of liquid chromatography-tandem mass spectrometry (LC-MS/MS) for detection of plasma free metanephrine (MN) and normetanephrine (NMN) and evaluated its analytical performance and clinical efficacy in differential diagnosis of adrenal incidentaloma. After solid-phase extraction, chromatographic isolation of the analytes and internal standard was achieved by column elution in the LC-MS/MS system. The analytes were detected in multiple-reaction monitoring mode by using positive electrospray ionization: MN, transition m/z 180.1-->165.1; NMN, m/z 166.1-->134.1. This method was validated for linearity, precision, accuracy, lower limits of quantification and detection, extraction recovery, and the matrix effect. Plasma concentrations of MN and NMN of 14 patients with pheochromocytoma were compared with those of 17 healthy volunteers, 10 patients with essential hypertension, and 60 patients with adrenal adenoma. The assay's linear range was 0.04-50.0 and 0.08-100.0 nmol/L for MN and NMN, respectively. Assay imprecision was 1.86-7.50%. The accuracy ranged from -7.50% to 2.00%, and the mean recovery of MN and NMN was within the range 71.5-95.2%. Our LC-MS/MS method is rapid, accurate, and reliable and useful for differential diagnosis of adrenal incidentaloma.
Adenoma ; Diagnosis, Differential* ; Healthy Volunteers ; Humans ; Hypertension ; Mass Spectrometry* ; Metanephrine ; Normetanephrine ; Pheochromocytoma ; Plasma*

BACKGROUND: Current guidelines for follow-up of adrenal incidentalomas are extensive and hampered by lack of follow-up studies. We tested the hypothesis that small lipid-rich adrenal incidentalomas, initially characterized by tumor size <40 mm and <10 Hounsfield units (HUs) on unenhanced computed tomography (CT) may not demonstrate excessive growth/hormonal hypersecretion on follow-up. METHODS: Sixty-nine incidentalomas in 56 patients were restudied with unenhanced CT and screening for hypercortisolism (dexamethasone suppression test [DST], plasma adrenocorticotropic hormone) and pheochromocytoma (24-hour urinary metanephrines and normetanephrines) 5 years later. Primary hyperaldosteronism was excluded at base-line. RESULTS: Tumor (n=69) size was similar before and after 5 years follow-up (19+/-6 mm vs. 20+/-7 mm). Mean tumor growth was 1+/-2 mm. Largest increase in tumor size was 8 mm, this tumor was surgically removed and histopathology confirmed cortical adenoma. DST was normal in 54 patients and two patients (3.6%) were still characterized by subclinical hypercortisolism. Initial tumor size was >20 mm for the patient with largest tumor growth and those with subclinical hypercortisolism. All patients had normal 24-hour urinary metanephrines and normetanephrines. Low attenuation (<10 HU) was demonstrated in 97% of 67 masses re-evaluated with unenhanced CT. CONCLUSION: None of the patients developed clinically relevant tumor growth or new subclinical hypercortisolism. Biochemical screening for pheochromocytoma in incidentalomas demonstrating <10 HU on unenhanced CT is not needed. For such incidentalomas <40 mm, it seems sufficient to perform control CT and screen for hypercortisolism after 5 years.
Adenoma ; Cushing Syndrome ; Follow-Up Studies* ; Humans ; Hyperaldosteronism ; Mass Screening ; Metanephrine ; Normetanephrine ; Pheochromocytoma ; Plasma ; Prospective Studies*

OBJECTIVE: Plasma free metanephrines (MNs) have been widely used as an initial test for pheochromocytoma and paraganglioma (PPGL). PPGL without MNs elevation has been reported on rare occasions. The objective of this study was to analyze the clinical profile of sporadic PPGL patients with normal MNs. METHODS: In the study, 104 patients with sporadic PPGL diagnosed by histopathology in Peking University First Hospital from March 2015 to January 2020 were enrolled. All the patients had plasma MNs result, of whom, eight (7.69%) were with normal MNs. The reasons for their medical visits, clinical manifestations, the levels of plasma free MNs, 3-methoxytyramine (3-MT), catecholamines and chromogranin A (CgA), and the imaging findings were documented. Their preoperative diagnosis, perioperative medical management, and intraoperative blood pressure were analyzed. All the data mentioned above were compared with the MNs elevated group. The postoperative follow-up for MNs normal patients were applied. RESULTS: For the eight PPGL patients with normal plasma MNs, the most common clinical symptoms were sweating (3/8), abdominal and back pain (3/8), headache (2/8), palpitations (2/8), and fatigue (2/8). There were no significant differences in plasma free 3-MT and catecholamines' diagnostic positive rate between the MNs normal group and MNs elevated group, but the rate for plasma CgA was significantly decreased in the MNs normal group (2/5 vs. 41/43, P=0.005). No significant difference was found for the incidence of typical findings by enhanced CT between the two groups. In these eight MNs normal patients, six were diagnosed with PPGL by the previous history of PPGL, typical symptoms and CT findings, or elevation of 3-MT, CgA levels or positive results of PET-CT; two patients were misdiagnosed as nonfunctioning adenoma or primary aldosteronism. All these MNs normal patients underwent preoperative management with alpha adrenergic receptor blockers, of whom, one had an average intraoperative arterial pressure < 60 mmHg during surgery. The median follow-up time for the eight patients was 1.5 (0.5－4.5) years. No evidence of new tumors was found on the enhanced CT scans. Two MNs normal patients' plasma 3-MT and (or) CgA decreased to normal. CONCLUSION For patients with adrenal or retroperitoneal tumors, typical symptoms or a previous history of PPGL, normal plasma MNs is not a sufficient exclusion for PPGL. Plasma 3-MT, catecholamine, CgA results and the imaging findings are helpful for the diagnosis of PPGL. We recommend patients with suspected MNs normal PPGL take alpha adrenergic receptor blockers as preoperative blockade, but should avoid overdose. Postoperative follow-up for patients with normal MNs should focus on the positive biochemical markers before surgery.
Adrenal Gland Neoplasms ; Humans ; Metanephrine ; Paraganglioma ; Pheochromocytoma ; Positron Emission Tomography Computed Tomography

Pheochromocytoma is usually associated with a combination of various clinical manifestations caused by the overproduction of catecholamines. It is frequently accompanied by impaired glucose tolerance operating through 2-and-adrenergic mechanisms. A 41-year-old-woman was admitted to the hospital because of poorly-controlled diabetes mellitus and hypertension. She had suffered intermittent paroxysmal attacks of headache and chest discomfort and had been treated intermittently over a 2 year period for diabetes mellitus and hypertension. At admission, the levels of serum epinephrine, norepinephrine urinary excretion of total metanephrine, and VMA were all abnormally elevated. Adrenal CT showed a well-defined, homogenous mass in the right adrenal region and the tumor was diagnosed as pheochromocytoma. After tumor resection, the increased blood level of catecholamines, the urinary excretion of total metanephrine, and VMA were normalized, as was the hyperglycemia state. Diabetes mellitus of the patient was considered permanently resolved after tumor removal by the result of glucose tolerance in 75g oral glucose tolerance test.
Catecholamines ; Diabetes Mellitus* ; Epinephrine ; Glucose ; Glucose Intolerance ; Glucose Tolerance Test ; Headache ; Humans ; Hyperglycemia ; Hypertension ; Metanephrine ; Norepinephrine ; Pheochromocytoma* ; Thorax

Despite all technical progress in modern diagnostic methods and treatment modalities of pheochromocytoma/paraganglioma, early consideration of the presence of these tumors remains the pivotal link towards the best possible outcome for patients. A timely diagnosis and proper treatment can prevent the wide variety of potentially catastrophic cardiovascular complications. Modern biochemical testing should include tests that offer the best available diagnostic performance, measurements of metanephrines and 3-methoxytyramine in plasma or urine. To minimize false-positive test results particular attention should be paid to pre-analytical sampling conditions. In addition to anatomical imaging by computed tomography (CT) or magnetic resonance imaging, new promising functional imaging modalities of photon emission tomography/CT using with somatostatin analogues such as ⁶⁸Ga-DOTATATE (⁶⁸Ga-labeled DOTA(0)-Tyr(3)-octreotide) will probably replace ¹²³I-MIBG (iodine-123-metaiodobenzylguanidine) in the near future. As nearly half of all pheochromocytoma patients harbor a mutation in one of the 14 tumor susceptibility genes, genetic testing and counseling should at least be considered in all patients with a proven tumor. Post-surgical annual follow-up of patients by measurements of plasma or urinary metanephrines should last for at least 10 years for timely detection of recurrent or metastatic disease. Patients with a high risk for recurrence or metastatic disease (paraganglioma, young age, multiple or large tumors, genetic background) should be followed up lifelong.
Catecholamines ; Counseling ; Diagnosis ; Follow-Up Studies ; Genetic Testing ; Humans ; Magnetic Resonance Imaging ; Metanephrine ; Paraganglioma* ; Pheochromocytoma* ; Plasma ; Recurrence ; Somatostatin

A 53-year-old woman had a 1.7 cm left adrenal mass on an abdominal computed tomography (CT) scan. She presented with paroxysmal headache, palpitation, sweating, and hypertension. The patient was highly suspected of having a pheochromocytoma, but measurements of 24-hour urinary metanephrine, catecholamines, and vanillylmandelic acid were normal. Plasma and urine catecholamine levels were within the normal range even during paroxysmal episodes. A scintigraphic study with 131I-metaiodobenzylguanidine (MIBG) revealed selective concentration of the radiotracer, corresponding to the CT mass. The patient underwent a left adrenalectomy and the pathological examination confirmed the diagnosis of pheochromocytoma. In this report, we describe a rare case of a symptomatic pheochromocytoma with normal catecholamine levels. Our case illustrates that routine nuclear scintigraphy, such as 131I-MIBG, should be performed even in cases with normal hormonal testing for all patients with high clinical suspicion of pheochromocytoma.
3-Iodobenzylguanidine ; Adrenalectomy ; Catecholamines ; Female ; Headache ; Humans ; Hypertension ; Metanephrine ; Middle Aged ; Pheochromocytoma ; Plasma ; Reference Values ; Sweat ; Sweating ; Vanilmandelic Acid

The coexpression of cortical and medullary features in a single adrenal cortical cell has been recognized, leading to terms such as cortico-medullary cells. Here, we reported a case of adrenocortical adenoma consisting of cortico-medullary cells that clinically mimicked pheochromocytoma. A 52-year-old woman was admitted to our hospital complaining of an 8-month history of paroxysmal palpitation with refractory hypertension. A 24-hour urine study revealed increased norepinephrine and metanephrine levels. Computed tomography of the abdomen revealed a 1.0x0.9-cm mass in the left adrenal gland. The patient subsequently underwent unilateral laparoscopic adrenalectomy for a presumptive pheochromocytoma. Light microscopic findings of the left adrenal mass indicated an adrenocortical adenoma, but electron microscopy identified lipid vacuoles and smooth endoplasmic reticulum, along with dense core neurosecretory granules, so-called cortico-medullary cells. This is the first report of the detection of cortico-medullary cells in adrenocortical adenoma presenting as pheochromocytoma in Korea.
Abdomen ; Adrenal Glands ; Adrenalectomy ; Adrenocortical Adenoma ; Endoplasmic Reticulum, Smooth ; Female ; Humans ; Hypertension ; Light ; Metanephrine ; Microscopy, Electron ; Middle Aged ; Norepinephrine ; Pheochromocytoma ; Vacuoles

The coexistence of extraadrenal pheochromocytoma and renal artery stenosis is extremely rare. The mechanisms of renal artery stenosis with pheochromocytoma include direct compression of the tumor mass on the renal artery and catecholamine-induced vasospasm, fibromuscular hyperplasia, and fibrous adhesion. We report a rare case of renal artery stenosis caused by extraadrenal pheochromocytoma in a 29- year-old female. She was admitted to the hospital because of palpitation and headache. She had been treated for hypertension for 2 years. On admission, her plasma epinephrine and norepinephrine levels were elevated as were her plasma renin activity, urinary vanillylmandelic acid (VMA) and metanephrine levels. Through the use of abdominal computed tomography, 131I-MIBG scan, and renal arteriography, a mass was found in the hilus of the left kidney which affected left renal artery stenosis. Surgical removal of the mass and left kidney restored the catecholamine excretion, plasma renin activity, and blood pressure to normal. Electronmicroscopic examination of the mass confirmed the pheochromocytoma.
Angiography ; Blood Pressure ; Epinephrine ; Female ; Headache ; Humans ; Hyperplasia ; Hypertension ; Kidney ; Metanephrine ; Norepinephrine ; Pheochromocytoma* ; Plasma ; Renal Artery Obstruction* ; Renal Artery* ; Renin ; Vanilmandelic Acid

An increasing number of incidental adrenal masses are found during the evaluation for unrelated problems, which is the result of the development of sensitive noninvasive methods for the imaging of abdominal lesions, such as ultrasonography, computed tomographic scanning, and MRI. When there is no evidence of adrenocortical or medullary dysfunction for such adrenal masses, they are commonly referred to as "incidentalomas". Among these incidentalomas, adrenal myelolipoma is a rare, benign, endocrinologically inactive tumor, the histological structure of which consists of mature adipose tissue cells and normal hemopoietic tissues resembling bone marrow. Even though most eventually prove to be nonhyperfunctioning adrenocortical adenomas, we must not exclude a more serious pathology. Because of the rarity of adrenal myelolipoma, its natural history, proper prognostic considerations and treatment recommendations still need to be investigated. We experienced 46 year-old man with abdominal discomfort, and a 26 year-old man with no specific symptoms, have large incidentalomas (>5 cm) in adrenal sites, detected by abdominal sonography for routine health work-up. The ACTH, cortisol, renin, aldosterenone, metanephrine, VMA and tumor marker levels were normal, which was suggestive of nonfunctional adrenal tumors. Surgical treatments were performed for rule out malignant adrenal tumors due to the tumor size (>5 cm) and hemorrhage within the tumors. The surgical pathology was that of adrenal myelolipomas. An adrenal myelolipoma is a rare, benign, nonfunctional adrenal tumor, but only three cases have been reported in Korea. We report two cases of adrenal myelolipoma found incidentally by surgical treatment for a large tumor size (>5 cm).
Adipose Tissue ; Adrenocortical Adenoma ; Adrenocorticotropic Hormone ; Adult ; Bone Marrow ; Hemorrhage ; Humans ; Hydrocortisone ; Korea ; Magnetic Resonance Imaging ; Metanephrine ; Middle Aged ; Myelolipoma* ; Natural History ; Pathology ; Pathology, Surgical ; Renin ; Ultrasonography