eMedicine Specialties > Endocrinology > Adrenal Gland

Pheochromocytoma: Differential Diagnoses & Workup

Author: Ann T Sweeney, MD, Associate Professor, Department of Medicine, Division of Endocrinology, Tufts University School of Medicine
Coauthor(s): Michael A Blake, MRCPI, FRCR, Assistant Professor, Department of Radiology, Harvard Medical School; Staff Radiologist, Division of Abdominal Imaging, Massachusetts General Hospital
Contributor Information and Disclosures

Updated: Jul 31, 2009

Differential Diagnoses

Other Problems to Be Considered

Alcohol withdrawal
Labile essential hypertension
Hyperventilation
Orthostatic hypotension
Multiple pharmacologic agents (monoamine oxidase inhibitors [MAOIs], decongestants, sympathomimetics)
Illegal drug use (phencyclidine [PCP], lysergic acid diethylamide [LSD], cocaine)
Migraine headache
Autonomic neuropathy
Stroke
Toxemia of pregnancy
Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome

Workup

Laboratory Studies

• The choice of diagnostic test should be based on the clinical suspicion of a pheochromocytoma. Plasma metanephrine testing has the highest sensitivity (96%) for detecting a pheochromocytoma, but it has a lower specificity (85%).⁶ In comparison, a 24-hour urinary collection for catecholamines and metanephrines has a sensitivity of 87.5% and a specificity of 99.7%.⁷
  • High-risk patients, including those who have a genetic syndrome that predisposes them to pheochromocytoma (eg, MEN 2A or 2B, VHL disease or neurofibromatosis, a prior history of a pheochromocytoma, a family history of a pheochromocytoma), should be screened with plasma metanephrine testing. In these scenarios, a higher-sensitivity test that lacks specificity is justified.
  • A fractionated plasma free metanephrine level may be measured in a standard venipuncture sample taken from a seated, ambulatory patient.
  • Patients at lower risk for a pheochromocytoma, including those with flushing spells, poorly controlled hypertension, or adrenal incidentalomas with an adrenocortical appearance, should be screened with a 24-hour urine collection for catecholamines and metanephrines. This test has a high specificity and acceptable sensitivity.
• Perform a 24-hour urine collection for creatinine, total catecholamines, vanillylmandelic acid, and metanephrines.
  • Measure creatinine in all collections of urine to ensure adequacy of the collection.
  • The collection container should be dark and acidified and should be kept cold to avoid degradation of the catecholamines.
  • Metanephrine levels are considered the most sensitive and specific test for a pheochromocytoma, while vanillylmandelic acid is the least specific test and has a false-positive rate greater than 15%.
  • Some authors have good experience with evaluating epinephrine and norepinephrine separately (in part to confirm the total catecholamine level and in part to determine whether levels reflect the high norepinephrine-to-epinephrine ratio expected) and, for the same reason, normetanephrines.
  • Dopamine levels are not useful in this test because most of the dopamine is of renal origin.
  • Optimally, collect urine during or immediately after a crisis.
  • Major physical stress and multiple drugs may interfere with the assay and cause false elevations of the metanephrines. These drugs include tricyclic antidepressants, levodopa, labetalol, ethanol, sotalol, amphetamines, buspirone, benzodiazepines, methyldopa, and chlorpromazine.
  • Compounds that decrease 24-hour urine levels of metanephrines are methyltyrosine, which inhibits tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthesis; methylglucamine, which is present in radiocontrast media; and reserpine.
• Provocative testing, although used in the past, rarely is needed. Agents used in the past to provoke a catecholamine surge include histamine, tyramine, glucagon, and metoclopramide. Suppression tests using phentolamine and clonidine can also be used for diagnostic purposes.
• Chromogranin A is an acidic monomeric protein that is stored with and secreted with catecholamines. Plasma levels of chromogranin A reportedly are 83% sensitive and 96% specific for identifying a pheochromocytoma. Chromogranin A levels are sometimes used to detect recurrent pheochromocytomas.

Imaging Studies

• Over 90% of pheochromocytomas are located within the adrenal glands, and 98% are within the abdomen. Extra-adrenal pheochromocytomas develop in the paraganglion chromaffin tissue of the sympathetic nervous system. They may occur anywhere from the base of the brain to the urinary bladder. Common locations for extra-adrenal pheochromocytomas include the organ of Zuckerkandl (close to origin of the inferior mesenteric artery), bladder wall, heart, mediastinum, and carotid and glomus jugulare bodies.
• Imaging studies should be performed only after biochemical studies have confirmed the diagnosis of pheochromocytoma. Magnetic resonance imaging (MRI) is preferred over computed tomography (CT) scanning. MRI has a reported sensitivity of up to 100% in detecting adrenal pheochromocytomas, does not require contrast, and does not expose the patient to ionizing radiation. MRI is also superior to CT scanning for detecting extra-adrenal pheochromocytomas. Typically, (approximately 70% of cases), pheochromocytomas appear hyperintense on T2-weighted images because of their high water content. (See image below and Image 1.)

• CT scanning of the abdomen has an accuracy of 85-95% for detecting adrenal masses with a spatial resolution of 1 cm or greater. (See image below and Image 2.) CT scanning is less accurate for lesions smaller than 1 cm. Differentiating an adenoma from a pheochromocytoma is more difficult using CT scanning. While most pheochromocytomas have CT attenuation greater than 10 Hounsfield units (HU), they rarely contain sufficient intracellular fat to have an attenuation of less than 10 HU. In addition, most pheochromocytomas have enhancement loss that is similar to that of adrenal metastases and significantly less than that of adrenal adenomas. However, in patients in whom pheochromocytomas are strongly suspected, adrenal pheochromocytomas cannot be entirely excluded from the list of differential diagnoses of adrenal neoplasms with less than 10-HU attenuation value and greater than 60% washout on delayed scanning.
  
  Although it has been thought that the use of intravenous contrast poses a risk of inducing hypertensive crisis in patients with pheochromocytomas, a controlled, prospective study in patients receiving low-osmolar CT contrast⁸ and a retrospective review in patients who received nonionic contrast⁹ concluded that this use of contrast is safe, even in patients not receiving alpha or beta blockers.

• A scan with iodine-131 (¹³¹ I) – labeled metaiodobenzylguanidine (MIBG) is reserved for cases in which a pheochromocytoma is confirmed biochemically but CT scanning or MRI does not show a tumor. The molecular structure of iodine-123 (¹²³ I) MIBG resembles norepinephrine and concentrates within adrenal or extra-adrenal pheochromocytomas. This isotope has a short half-life and is expensive. It frequently is used in cases of familial pheochromocytoma syndromes, recurrent pheochromocytoma, or malignant pheochromocytoma. In the United States, only¹³¹ I-labeled MIBG is available, whereas¹²³ I MIBG is used in Europe and Japan.
• A somatostatin receptor analog indium-111 (¹¹¹ In) pentetreotide is less sensitive than MIBG and may be used to visualize pheochromocytomas that do not concentrate MIBG.
• Positron emission tomography (PET) scanning has been used as an imaging modality and has shown promising results. PET with 18F-fluorodeoxyglucose, which is selectively concentrated as part of the abnormal metabolism of many neoplasms, has been demonstrated to detect occult pheochromocytomas. Pheochromocytomas usually show increased uptake on PET scanning, as do adrenal metastases. The most impressive results to date have been with 6-[18F] fluorodopamine PET scanning and carbon-11 hydroxyephedrine PET scanning. Results of these studies suggest that PET scanning performed with both of these radioisotopes is extremely useful in the detection and localization of pheochromocytomas. Further study results with these agents are eagerly awaited.
• Initial studies have suggested that MR spectroscopy can be used to distinguish pheochromocytomas from other adrenal masses.^10,11 Specifically, a resonance signature of 6.8 ppm appears to be unique to pheochromocytomas; the signature apparently is attributable to the catecholamines and catecholamine metabolites present in pheochromocytomas.¹¹

Other Tests

• Once the diagnosis of pheochromocytoma is made, perform additional studies to rule out a familial syndrome, such as MEN 2A or 2B.
  • Obtain a serum intact parathyroid hormone level and a simultaneous serum calcium level to rule out primary hyperparathyroidism (part of MEN 2A).
  • Obtain a serum calcitonin level. Some investigators advocate a pentagastrin infusion test; however, genetic screening tests for the ret proto-oncogene may obviate the need for this provocative test.
  • Perform screening for mutations in the ret proto-oncogene in any patient with a familial syndrome or to distinguish a sporadic pheochromocytoma from a familial pheochromocytoma.⁵ Mutation analysis involves amplification of sequences, including exons 10, 11, 13, 14, and 16 of the ret proto-oncogene from the patient's genomic DNA, followed by sequence analysis. Particular attention is given to specific sequences for the codons known to be hot spots for mutations causing the MEN 2A and 2B syndromes. Over 95% of cases of MEN 2A and 85% of cases of familial medullary thyroid cancer are associated with mutations affecting 1 of 5 codons in exon 10 (codon 609, 611, 618, and 620) or exon 11 (codon 634). Over 95% of individuals with MEN 2B have a germline mutation in codon 918 of exon 16.
  • Obtain a consultation with an ophthalmologist to rule out retinal angiomas, and consider brain MRI to exclude cerebellar hemangioblastomas (VHL disease).
  • Obtain a CT scan of the kidneys and pancreas to rule out cysts.
• Patients with seizures, unexplained shock, weight loss, cardiomyopathy, neurofibromatosis, and/or orthostatic hypotension should be screened for pheochromocytomas.

Procedures

• Because of the high sensitivity of MRI and CT scanning, procedures are rarely indicated for localization of pheochromocytomas.
  • Selective venous sampling is seldom performed to localize pheochromocytomas but has occasionally been used to detect extra-adrenal pheochromocytomas that were not found at surgery. This procedure generally is not helpful in detecting extra-adrenal tumors because catecholamine levels have marked variability. An exception to this rule, however, occurs if the norepinephrine concentration is greater than the epinephrine concentration in the venous effluent. Because the primary catecholamine produced and stored in the adrenal gland is epinephrine, a ratio of norepinephrine to epinephrine that is greater than 1 suggests a pheochromocytoma.
  • Arteriography is rarely indicated. It provides little additional information compared with MRI or CT scanning and the use of radiocontrast dye may induce a hypertensive crisis.

Histologic Findings

Pheochromocytomas vary from 2 g to 3 kg but, on average, weigh 100 g (healthy adrenal gland weighs 4-6 g). These tumors are well encapsulated, highly vascular, and appear reddish brown on cut section.

Histologically, the tumor cells are arranged in balls and clusters separated by endothelial-lined spaces; this classic pattern characteristic of pheochromocytoma is termed zellballen. The cells vary in size and shape and have finely granular basophilic or eosinophilic cytoplasm. The nuclei are round or oval with prominent nucleoli. Nuclear giantism and hyperchromasia are common.

Staging

Approximately 10% of pheochromocytomas are malignant. Direct invasion of surrounding tissue or the presence of metastases determines malignancy. Unfortunately, no reliable clinical, biochemical, or histological features distinguish a malignant from a benign pheochromocytoma. Factors that suggest a malignant course include large tumor size and DNA ploidy pattern (aneuploidy, tetraploidy). Common metastatic sites include bone, liver, and lymph nodes.

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