Chairman, National Hypertension Association Professor of Clinical Medicine, New York University Medical Center New York, New York 10016
Address all correspondence and requests for reprints to: William M. Manger, M.D., Ph.D., National Hypertension Association, Inc., 324 E. 30th Street, New York, New York 10016.
Diagnosing and locating pheochromocytomas can be a daunting and challenging experience for clinicians, because these tumors secrete catecholamines and can mimic a variety of other diseases and because the primary tumors can occur in so many different locations. Pheochromocytomas arise from chromaffin cells of the sympathoadrenal system. Ninety-eight percent of these tumors occur in the abdomen (mainly in the adrenal medulla but also in the organ of Zuckerkandl and in cells adjacent to sympathetic nerves) and pelvis (including the urinary bladder); less than 2% occur in the chest (usually in cells near the paraspinal areas but occasionally in the mediastinum and heart); about 0.2% occur in the neck (in the carotid body or jugular foramen); very rarely, they occur in exotic locations (at the base of the skull, middle ear, and spermatic cord) (1). Occasionally, pheochromocytomas occur bilaterally in the adrenal glands, especially if they are familial, or they may arise multifocally and remain benign or become malignant.
The diagnosis of pheochromocytoma should always be considered in patients with sustained or paroxysmal hypertension, especially if there are any manifestations of excess circulating catecholamines (e.g. hypertension accompanied by headaches, palpitations with or without tachycardia, inappropriate and generalized sweating, pallor, tremor, extreme anxiety, and hyperglycemia). Clinical manifestations may appear episodically every day or week or only every few months; usually they last for minutes or hours and then gradually subside, leaving the individual exhausted (1, 2). A previous history of a pheochromocytoma, evidence of neurofibromatosis, multiple endocrine neoplasia type 2A or 2B, von Hippel-Lindau disease, or a family history of any of these diseases should alert the clinician to search for a pheochromocytoma.
Pheochromocytoma is a very treacherous tumor that has been likened to a pharmacological bomb that may suddenly secrete massive amounts of catecholamines into the circulation and cause marked elevations of blood pressure; if not promptly recognized and appropriately treated, it almost invariably causes fatal cardiovascular disease. Furthermore, 1013% of these tumors are malignant, and metastases may occur in the lungs, liver, lymph nodes, and bone, but not in the brain (1). Approximately 85% of pheochromocytomas occur in the adrenal medulla, whereas up to 18% have been reported in extraadrenal locations (3). Extraadrenal pheochromocytomas (also termed paragangliomas) reportedly have at least three times greater prevalence of malignancy than adrenal pheochromocytomas (1).
The key to diagnosis is first to think of this relatively rare neuroendocrine tumor. Experience with measuring plasma metanephrines and/or urinary metanephrine and normetanephrine indicates that these catecholamine metabolites are almost always elevated in individuals harboring a pheochromocytoma; their sensitivity in detecting these tumors approaches 99% and 97%, respectively (4). However, in some patients with familial pheochromocytoma clinical manifestations may be absent, and all biochemical testing may remain normal. Occasionally, tests may be falsely elevated in patients without a pheochromocytoma. When this is a concern, further biochemical testing, sometimes combined with the clonidine suppression test, is indicated to eliminate the presence of a pheochromocytoma (1, 5).
The report in this journal by Ilias et al. (6) demonstrates the remarkable sensitivity of 6-[18F]fluorodopamine ([18F]DA) positron emission tomography (PET) in localizing metastatic pheochromocytomas. This relatively new nuclear imaging technique is a most welcome addition, because it improves the ability to detect pheochromocytomas in the pelvis, abdomen, chest, and neck and also to identify metastases not always visible by other imaging modalities.
Pheochromocytomas were identified by [18F]DA PET in all 16 patients studied; computed tomography (CT) and/or magnetic resonance imaging (MRI) revealed findings consistent with pheochromocytoma in 15 of these patients, but [131I]metaiodobenzylguanidine (MIBG) identified metastatic tumors in only nine of the 16 patients, indicating a sensitivity of 56%. The authors point out that [18F]DA is a better substrate for the norepinephrine transporter than other amines and MIBG; this probably explains the remarkable sensitivity of [18F]DA over other nuclear imaging techniques in detecting pheochromocytomas. The results clearly establish the superiority of [18F]DA PET over [131I]MIBG in detecting metastatic pheochromocytomas. Other radiopharmaceuticals have been used to detect pheochromocytomas by scintigraphy, but results have been disappointing because of poor sensitivity and/or specificity; however, initial results using [18F]dihydroxyphenylalanine ([18F]DOPA) appear promising, but studies with this agent comprised only a small number of benign pheochromocytomas (7). 111Indium octreotide, which depends on the presence of somatostatin receptors in tumor cells, detects only 25% of benign pheochromocytomas; however, it may occasionally locate metastatic lesions that are missed by [123I]MIBG (8).
The sensitivity of detecting adrenal pheochromocytomas 1 cm or greater approaches 100% and 95% by MRI and CT, respectively; however, Ilias et al. (6) indicate that the sensitivity for detecting extraadrenal, metastatic, or recurrent pheochromocytoma may be less than 91% by either of these imaging techniques. CT requires oral and iv contrast for optimal interpretation, and previous operations can significantly impair detection by CT of recurrent pheochromocytomas, because of interfering artifactual distortions caused by surgical clips (1). MRI is noninvasive, and CT artifacts caused by surgical clips are not encountered; it appears superior to CT in detecting extraadrenal abdominal and pelvic lesions and some cardiac and familial adrenal pheochromocytomas (1, 2). Although MRI provides a characteristic image that is quite specific for pheochromocytomas in the majority of these tumors, CT offers no specificity. In contrast, specificity of 95100% is provided by [131I]MIBG, which detects about 80% of primary pheochromocytomas. This remarkable specificity also applies to [123I]MIBG, which is just becoming available for use in the United States, and its sensitivity is reported to be about 90%, making it superior to [131I]MIBG. A comparison between [123I]MIBG, [18F]DA, and [18F]DOPA should be performed to assess their sensitivities in detecting both primary and metastatic pheochromocytomas. Nuclear imaging can be especially useful in determining whether an incidentaloma is a pheochromocytoma. A large survey revealed that 4.2% of incidentalomas were pheochromocytomas, but only 43% of these patients were hypertensive, despite urinary catecholamine elevations in 86% (9).
It must be appreciated that MIBG uptake may also occur in neuroblastomas, medullary thyroid carcinomas, carcinoids, and small cell lung carcinomas. Because medullary carcinoma coexists in some patients with familial pheochromocytoma in the multiple endocrine neoplasia syndromes, it is important to determine whether metastases are due to malignant pheochromocytoma or medullary thyroid carcinoma. This may rarely require biopsy of metastases to establish an accurate diagnosis. Whether [18F]DA is taken up by tumors other than pheochromocytoma and neuroblastoma remains to be studied; localization of a medullary thyroid carcinoma metastasis with this agent has recently been reported (10).
It is noteworthy that update of MIBG may be inhibited by certain drugs (e.g. labetalol, reserpine, calcium channel blockers, tricyclic antidepressants, sympathomimetics, cocaine, adrenergic neuron blockers, and tranquilizers), and these drugs should be discontinued 1 week before scintigraphy (1, 2). Many of these drugs may interfere with the uptake of [18F]DA, but additional observations on the effects of these agents on uptake of this radioactive agent are required.
Detection of pheochromocytoma metastases is extremely important, because it usually determines whether removal of the primary tumor is indicated or whether chemotherapy and/or radiotherapy and prolonged antihypertensive treatment is required; it also provides valuable prognostic information that can be conveyed to patients and their families. Almost 90% of primary pheochromocytomas can be removed successfully by laparoscopy or a transperitoneal or flank approach.
Advantages of [18F]DA PET over [131I]MIBG are:
1. Imaging with [18F]DA requires less radiation than [131I]MIBG scanning.
2. No adverse thyroid effects are caused by [18F]DA, and there is no need for pretreatment with potassium iodide, which is essential to protect the thyroid when imaging with [131I]MIBG.
3. Imaging with [18F]DA can be performed immediately (because of the rapid uptake of this catecholamine), whereas a delay of 2448 h is necessary (for disappearance of background radiation to permit optimal visualization) for imaging with [131I]MIBG, which is not a catecholamine.
4. [18F]DA PET scanning yields images superior to [131I]MIBG imaging.
Currently [18F]DA imaging is only available at the National Institutes of Health, and the cost of imaging with this agent may be about twice that of [131I]MIBG. One advantage of [131I]MIBG or [123I]MIBG is that the entire body is scanned, whereas [18F]DA is usually limited to imaging from the neck to the pelvis; however, if indicated, the entire body can be imaged with [18F]DA. In the present study, 10 metastatic lesions in four patients were identified by [131I]MIBG, but nine of these metastases (in the head and lower extremities) were not imaged with [18F]DA. Only one abdominal lesion was identified by [131I]MIBG but not by [18F]DA. Occasionally, bone scanning with technetium may demonstrate metastatic lesions missed by [131I]MIBG (1).
[18F]DA has been shown previously to be a highly sensitive nuclear imaging modality for localizing pheochromocytomas (11, 12). It seems likely that this remarkable sensitivity also exists for detecting metastases; however, more experience with a large number of patients with metastatic pheochromocytomas will be necessary to firmly validate the authors results.
In general, the diagnosis of pheochromocytoma must first be established by demonstrating elevated plasma or urinary catecholamines and/or their metabolites that are not false positives, i.e. caused by other conditions. Rarely, in some subjects suspected of having familial pheochromocytoma, which accounts for about 15% of these tumors, it is justifiable to perform imaging studies without biochemical evidence of tumor, because some familial tumors may be identified before they secrete significant amounts of catecholamines. The tumor(s) must next be located. MRI is preferable to CT in localizing the site of the primary tumor(s) and is superior to CT in localizing most extraadrenal pheochromocytomas and their metastases; however, it cannot establish that the tumor is a pheochromocytoma. Therefore, whenever available, nuclear imaging should be performed to confirm that the tumors are pheochromocytomas and to determine whether metastases exist, because the results of this imaging can be of great value in guiding treatment and prognosis. (Any form of radiation should be avoided in a pregnant patient or a child; only MRI is permissible to search for a pheochromocytoma during pregnancy.) Currently, [131I[MIBG and [123I]MIBG are available only in some major medical centers in the United States. However, these may be replaced with the advent of [18F]DA, if this becomes generally available and also proves to be superior to [123I]MIBG.
Treatment of malignant pheochromocytoma with [131I]MIBG radiation alone or in addition to chemotherapy or x-ray radiation has provided beneficial effects for 23 yr in some patients (1, 13, 14); however, results usually have been disappointing, and only very rarely has a prolonged benefit or remission been reported. Radiation with [18F]DA would not be expected to have any significant beneficial effects in the treatment of malignant pheochromocytomas because of its low dosage and short duration of radiation.
Footnotes
Abbreviations: CT, Computed tomography; 6-[18F]DA, [18F]fluorodopamine; [18F]DOPA, [18F]dihydroxyphenylalanine; MIBG, metaiodobenzylguanidine; MRI, magnetic resonance imaging; PET, positron emission tomography.
Received July 15, 2003.
Accepted July 15, 2003.
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