 |
 |
|
|
|  PubMed
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
20 February 2001 | Volume 134 Issue 4 | Pages 315-329
Pheochromocytoma is a rare but important tumor of chromaffin cells that is frequently considered in the evaluation of hypertension, arrhythmias, or panic disorder and in the follow-up of patients with particular genetic diseases. This report provides an update about the genetics, neurochemical diagnosis, localization by imaging, and surgical management of pheochromocytoma. Specific mutations of the RETproto-oncogene cause familial predisposition to pheochromocytoma in multiple endocrine neoplasia type II, and mutations in the von Hippel–Lindau tumor suppressor gene cause familial disposition to pheochromocytoma in von Hippel–Lindau disease. Recent findings demonstrating extraordinarily high sensitivity of plasma levels of metanephrines for detecting pheochromocytoma have led to an algorithm for clinical diagnostic steps. Nuclear imaging approaches, such as 123I-metaiodobenzylguanidine scintigraphy and 6-[18F]fluorodopamine positron emission tomography, enhance both diagnosis and localization of the tumor, as described in an algorithm for patients with positive biochemical test results. Since pheochromocytoma is often benign, surgical resection by laparoscopic adrenalectomy can be curative. Areas requiring further work include determining appropriate follow-up of patients with familial pheochromocytoma, elucidating the bases for phenotypic differences, improving both specificity and sensitivity of biochemical tests, optimizing cost-effectiveness of diagnostic imaging, and testing the risk for tumor recurrence after partial adrenalectomy.
Hypertension, whether sustained or paroxysmal, is the most common clinical sign, and headache, excessive truncal sweating, and palpitations are the most common symptoms (1). Pallor is also common, whereas flushing occurs less frequently. Some patients present with severe episodes of anxiety, nervousness, or panic. Patients with a familial predisposition or small incidentally discovered adrenal masses can be normotensive and asymptomatic.
The low pretest prevalence of pheochromocytoma—close to 0.5% among those tested because of hypertension and suggestive symptoms (1) and as high as 4% in patients with adrenal incidentaloma (2)—together with imperfect sensitivity and specificity of commonly used biochemical and imaging tests, can make diagnosis and localization of pheochromocytoma difficult. Effective methods for diagnosis and localization are important because seemingly mild stimuli can provoke the tumor to release large amounts of catecholamines, with severe or fatal consequences. Moreover, surgical removal can cure pheochromocytoma in up to 90% of cases, whereas if left untreated the tumor can prove fatal.
Advances in genetic mutation analysis have greatly improved identification of patients with familial pheochromocytoma, allowing detection of tumors at an early stage, often before typical signs and symptoms occur. These advances provide new insights into the biology and natural history of the disease and highlight inadequacies of commonly used diagnostic tests. In turn, new developments have been made in the management of patients with familial pheochromocytoma and in surgical procedures for preserving normal adrenal cortical tissue in persons with bilateral adrenal tumors. In this paper, we summarize advances in the genetics, biochemical diagnosis, localization, and management of pheochromocytoma and also note key questions that remain unanswered. NIH CONFERENCE
Recent Advances in Genetics, Diagnosis, Localization, and Treatment of Pheochromocytoma
Dr. Karel Pacak (Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development [NICHD] and Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke [NINDS], National Institutes of Health [NIH], Bethesda, Maryland): Pheochromocytomas are chromaffin cell tumors that, although rare, must be considered in patients with hypertension, autonomic disturbances, panic attacks, adrenal incidentalomas, or familial diseases featuring a predisposition to develop pheochromocytoma.
Molecular Genetic Abnormalities Associated with Pheochromocytoma
Drs. W. Marston Linehan and McClellan M. Walther (Urologic Oncology Branch, National Cancer Institute [NCI], NIH, Bethesda, Maryland): Pheochromocytomas may be classified as sporadic or familial. Most pheochromocytomas are sporadic. Familial predisposition is seen mainly in patients with multiple endocrine neoplasia type II (MEN II), von Hippel–Lindau disease, neurofibromatosis type 1, and familial carotid body tumors (Table 1). The exact molecular mechanisms by which the hereditary mutations predispose to tumor development remain unknown. Hereditary forms of pheochromocytoma can differ in rate of tumor growth, malignant potential, and catecholamine phenotype.
|
Cancer Genes
Identification of a cancer gene can help us understand the origin of cancer, such as pheochromocytoma, and elucidate mechanisms of tumor formation and behavior. Moreover, identification of a disease gene provides a method for genetic diagnosis. Phenotypic manifestations of a hereditary cancer syndrome can vary markedly, and genetic tests can confirm the diagnosis when the clinical presentation is complex. Finally, understanding of cancer genes may provide targets for therapy.
The two most studied types of cancer genes are tumor suppressor genes (Figure 1) and oncogenes (7). When mutated, a proto-oncogene becomes "activated," resulting in an oncogene. This is referred to as a "single hit"; that is, the proto-oncogene undergoes a single activating mutation that turns it into an oncogene (8, 9). Familial predisposition to pheochromocytoma in patients with MEN II results from such a mechanism. In contrast, a tumor suppressor gene is a "loss-of-function" gene, in which inactivation of both copies of the gene causes unregulated cell growth and division. This loss of function can result from mutation of one allele of a tumor suppressor gene and deletion of the second copy (10). Examples of tumor suppressor genes are the retinoblastoma gene, the Wilms tumor gene, the tuberous sclerosis genes, and, in the case of pheochromocytoma, the von Hippel–Lindau gene (11-19).
|
Pheochromocytoma in Multiple Endocrine Neoplasia Type II: RETGene
Multiple endocrine neoplasia type IIA is characterized clinically by the familial association of medullary thyroid cancer, pheochromocytoma, and parathyroid hyperplasia. Mucosal ganglioneuromas are also found in some patients (MEN IIB). Pheochromocytoma in MEN II is associated with germline mutation of the proto-oncogene RET. This proto-oncogene becomes an oncogene when an activating mutation occurs (20-25). The activating mutation in the RETgene drives the abnormal cellular proliferation that leads to adrenal medullary hyperplasia and pheochromocytoma. Several RETgermline mutations are associated with the development of pheochromocytoma, with some variation dependent on the particular mutation (3-5, 26, 27) (Table 1).
Pheochromocytoma in von Hippel–Lindau Disease: the von Hippel–Lindau Gene
Patients with von Hippel–Lindau disease have a germline mutation of the von Hippel–Lindau gene (28). Affected persons can develop early-onset bilateral kidney tumors and cysts, pheochromocytomas, cerebellar and spinal hemangioblastomas, retinal angiomas, pancreatic cysts and tumors, epididymal cystadenomas, and tumors in the endolymphatic sac canal of the inner ear (29-31).
von Hippel–Lindau disease has marked phenotypic heterogeneity. While patients from some families present with central neural, eye, kidney, and pancreatic tumors, patients in other families present mainly with pheochromocytoma (30, 32, 33). Some reports have described families thought to have "familial pheochromocytoma" who proved to have von Hippel–Lindau disease (32, 34-37). Missense mutations in the von Hippel–Lindau gene are associated with the development of pheochromocytoma more than twice as often as are other types of mutations (74% vs. 32%) (6, 33).
Molecular Genetic Diagnosis
von Hippel–Lindau disease and MEN II have a similar prevalence (approximately 1 in 30 000 to 1 in 45 500). Mutations predisposing to pheochromocytoma have greater penetrance in MEN II than in von Hippel–Lindau disease (38, 39). Pheochromocytoma in von Hippel–Lindau families has been reported as familial pheochromocytoma or MEN II (40, 41). Because different kindreds can present with different phenotypes, it can be difficult to distinguish between von Hippel–Lindau disease and MEN II in some patients with familial pheochromocytoma. Patients with bilateral adrenal, recurrent, or multifocal pheochromocytoma should undergo clinical or genetic testing for mutations of the von Hippel–Lindau or RETgenes.
The availability of germline testing for both von Hippel–Lindau (42) and RET (15, 20, 23, 40, 43) gene mutations (at OncorMed in Gaithersburg, Maryland, and at the University of Pennsylvania in Philadelphia) has improved the clinical management of patients with hereditary pheochromocytoma. When a patient presents with a family history in which the primary manifestation is pheochromocytoma, the von Hippel–Lindau gene is a likely cause. Some von Hippel–Lindau families present mainly with pheochromocytoma and occult or delayed manifestations in the central nervous system, eye, or other organs. It is less likely that a member of a MEN II family will present predominantly with pheochromocytoma because most of these patients have medullary thyroid carcinoma (44). A small number of families with familial pheochromocytoma have neither von Hippel–Lindau nor RETgermline mutations, and the genetic basis for this is currently being studied.
Biochemical Diagnosis of Pheochromocytoma
|
|---|
Since catecholamines are normally produced by sympathetic nerves and by the adrenal medulla, high catecholamine levels are not specific to pheochromocytoma and may accompany other conditions or disease states. In addition, sometimes pheochromocytomas do not secrete enough catecholamines to produce positive test results or typical signs and symptoms. In addition, pheochromocytomas often secrete catecholamines episodically. Between episodes, levels of catecholamines may be normal. Thus, commonly used tests of plasma or urinary catecholamines and metabolites and other biochemical tests, such as measurements of plasma chromogranin A levels, do not always reliably exclude or confirm a tumor (45-55). A recently developed biochemical test, involving measurements of plasma levels of free metanephrines (o-methylated metabolites of catecholamines), circumvents many of the above problems and offers a more effective means to diagnose pheochromocytoma than other tests (46, 56).
Sensitivity of Biochemical Tests
Measurements of plasma levels of normetanephrine and metanephrine have higher sensitivity than other biochemical tests for diagnosis of both sporadic and familial pheochromocytoma (46, 56). In familial pheochromocytoma, periodic screening can lead to early-stage detection before symptoms and signs, when tumors are small and are not secreting large amounts of catecholamines (6). The difficulty of biochemical diagnosis of familial pheochromocytoma is illustrated by our findings of only 46% to 72% sensitivity for commonly used tests in 39 cases of familial pheochromocytoma, compared with a 97% sensitivity for plasma metanephrines (56). In our larger series of 151 patients with mainly sporadic pheochromocytoma, sensitivity of plasma metanephrines was greater than 99%, compared with only 63% to 85% for other tests (Table 2). Plasma metanephrines are also useful for diagnosis of pheochromocytoma in patients with adrenal incidentalomas. In one case of an asymptomatic and normotensive patient with a 5-cm adrenal incidentaloma, elevated plasma levels of metanephrines provided the only biochemical evidence of pheochromocytoma (57).
|
Specificity of Biochemical Tests
Any of a variety of physiologic, pharmacologic, or pathologic conditions can increase plasma and urinary catecholamine levels (58). Since upper reference limits of biochemical tests are usually established from the 95% confidence intervals of values in a reference population, a certain incidence of false-positive results is expected. In our series of 349 patients in whom pheochromocytoma was excluded, specificities were 80% to 94% (Table 2).
The probability of a positive test result indicating a pheochromocytoma can be estimated by using Bayesian inference in the form of likelihood ratios (59, 60). Probability also depends on the extent of the increase of the test result above normal, established by receiver-operating characteristic curves, in which the frequency of true-positive results at different upper reference limits is plotted against the frequency of false-positive results (46). At higher upper reference limits, although the sensitivity of a test is reduced, the specificity of the test and probability of pheochromocytoma indicated by a positive test result can both approach 100%.
Our experience shows that plasma concentrations of normetanephrine greater than 2.5 pmol/mL or metanephrine levels greater than 1.4 pmol/mL (> 4- and 2.5-fold above the upper reference limits) indicate a pheochromocytoma with 100% specificity. The few conditions in which plasma metanephrines can reach such levels (for example, monoamine oxidase deficiency) are easily excluded. As illustrated in Table 2, at the higher limits more specific for a tumor, plasma metanephrines are more effective in confirming a pheochromocytoma than other tests.
Procedural Recommendations
The most important consideration in choosing an initial biochemical test is the reliability of the test for exclusion of pheochromocytoma. In pheochromocytoma, a missed diagnosis due to a false-negative result can have catastrophic consequences for the patient, while a false-positive result can be refuted by further tests. Because of their uniquely high sensitivity, we recommend plasma metanephrines as the initial biochemical test. Since pheochromocytomas are rare, most tests will prove negative, reliably excluding pheochromocytoma so that no further tests are necessary (Figure 2). This compares favorably with other tests, which do not exclude all pheochromocytomas even when performed in combination (56). A single test of plasma metanephrines also minimizes problems associated with combinations of tests in which higher numbers of false-positive results require additional time and effort for follow-up.
|
|
As discussed earlier, the probability of whether a positive test result reliably confirms a pheochromocytoma can better be determined by consideration of receiver-operating characteristic curves. Our experience shows that more than 80% of patients with pheochromocytoma have elevated plasma metanephrine levels that indicate a pheochromocytoma with 100% specificity (Table 2, Figure 2). For these patients, the probability of pheochromocytoma is increased to close to 100% by a single test of plasma metanephrines. The immediate task then is to localize the tumor by using imaging studies; further biochemical testing is not necessary.
These considerations show that most patients with pheochromocytoma can be identified immediately by a single test of plasma metanephrines. However, as indicated in the algorithm (Figure 2), many patients have marginally elevated plasma levels of normetanephrine or metanephrine. Among this group, differentiating true-positive from false-positive results remains a problem. In such patients, it is important to review the clinical history and consider possible explanations for a false-positive result. Supplemental biochemical testing is then required, taking care to avoid conditions or medications that might lead to false-positive results.
Additional follow-up biochemical tests should include measurements of plasma catecholamines and repeated measurements of metanephrines (Figure 2). Since metanephrines are produced continuously by a pheochromocytoma, normal plasma levels of normetanephrine and metanephrine in a second test exclude pheochromocytoma, even if results of the first test or other tests are positive. If plasma metanephrines remain positive, then the pattern of alterations in other results can be helpful in planning a strategy for further testing.
The clonidine suppression test is useful for distinguishing between high levels of plasma norepinephrine caused by release from sympathetic nerves and those caused by release from a pheochromocytoma (61-67). A decrease of more than 50% in plasma norepinephrine levels or a decrease after clonidine administration to less than 2.96 nmol/L indicate normal responses, whereas consistently elevated concentrations before and after clonidine administration indicate a pheochromocytoma. When the above criteria for a normal response are used, the test is highly specific. However, in patients with intermittently secreting tumors or those in whom plasma norepinephrine concentrations are normal or only marginally elevated, plasma norepinephrine levels may decrease regardless of a tumor, resulting in a false-negative test result (61-63, 68). False-positive test results can occur in patients taking diuretics or tricyclic antidepressants (61, 69). However, except in these cases, clonidine rarely fails to decrease plasma norepinephrine levels in patients without pheochromocytoma.
The glucagon stimulation test can be useful when high plasma levels of normetanephrine or metanephrine are noted and plasma catecholamine levels are normal or moderately elevated. A greater than threefold increase in norepinephrine levels 2 minutes after intravenous administration of glucagon indicates a pheochromocytoma with high specificity (70, 71). However, the test is not sensitive, and a negative test result does not exclude pheochromocytoma.
Because of possible severe hypotension during the clonidine test and hypertension during the glucagon test, both tests are best performed by experienced clinicians. The value of both tests, when judiciously implemented and appropriately interpreted, is that they can indicate a pheochromocytoma with high specificity.
Appropriate biochemical testing, combined with assessment of clinical history, should in most cases provide sufficient evidence to exclude pheochromocytoma or justify imaging studies to locate the tumor. To minimize expensive and unnecessary imaging studies, it would be ideal if biochemical testing could confirm or exclude pheochromocytoma in every patient. In reality, however, follow-up imaging studies are often required in patients for whom biochemical evidence of pheochromocytoma is not definitive.
Advances in Diagnostic Localization of Pheochromocytoma
|
|---|
Computed tomography has good sensitivity (93% to 100%) for detecting adrenal pheochromocytoma (72-75). Sensitivity decreases to approximately 90% for extra-adrenal pheochromocytomas (76). In contrast, magnetic resonance imaging has lower or equal sensitivity for detecting adrenal pheochromocytomas but is superior for detecting extra-adrenal tumors (72, 73). Both imaging methods have poor specificity, as low as 50% in some studies (74). This is an important problem because of the relatively high frequency of adrenal masses that are not pheochromocytomas (74, 77).
Metaiodobenzylguanidine scanning offers superior specificity (95% to 100%) and is helpful in diagnosing extra-adrenal tumors. However, it is not sensitive enough (77% to 90%) to exclude pheochromocytoma (49, 74, 76-84). Currently, only 131I-metaiodobenzylguanidine is commercially available in the United States (85). 123I-metaiodobenzylguanidine offers superior image quality because the characteristic photon energy is well suited for cameras equipped with low-energy, high-resolution collimators and because it can be used with single-photon emission computed tomography. 123I-metaiodobenzylguanidine seems especially useful for detecting recurrent or metastatic pheochromocytoma, tumors with fibrosis or distorted anatomy, and tumors in unusual locations (86-88).
The limitations of routinely available imaging methods have led to evaluation of other radiotracers for diagnostic localization of pheochromocytoma (87, 89-91). A few reports noted expression of somatostatin receptors by pheochromocytoma cells (87, 89-91). Scintigraphy after administration of radiolabeled octreotide, an analogue of somatostatin, has had only limited success, depending on anatomic factors, expression of somatostatin receptors, and delivery of the radiopharmaceutical to the tumor cells.
Positron emission tomography is a physiologic method of imaging that depends on selective binding or uptake and retention of radiopharmaceuticals by different tissues. The use of short-lived positron-emitting radionuclides allows administration of large tracer doses, resulting in high count density, superior resolution, and a short imaging time frame. This enables visualization almost immediately after administration of the imaging agent. In contrast, metaiodobenzylguanidine scanning requires imaging for a 24- to 48-hour period (92).
Several imaging agents for positron emission tomography have been used to visualize primary and metastatic tumors (89, 93-96), such as pheochromocytoma (87, 92, 97). Uptake of 18F-fluorodeoxyglucose by cells with a relatively high metabolic rate can allow successful visualization of pheochromocytoma (91). A case of malignant pheochromocytoma in the anterior mediastinum was localized by positron emission tomography after administration of 82rubidium, which the body handles similarly to potassium (98). All rapidly metabolizing cells take up both 18F-fluorodeoxyglucose and 82rubidium, so neither can detect pheochromocytoma specifically. Thus, these approaches are not recommended for initial localization of pheochromocytoma.
More specific agents, such as 11C-hydroxyephedrine, might be expected to have less sensitivity than 18F-fluorodeoxyglucose because of the requirement of uptake by monoamine transporters (91, 92, 99). However, 18F-fluorodeoxyglucose and 11C-hydroxyephedrine have similar sensitivities for detection of pheochromocytoma (91). Positron emission tomography with 11C-hydroxyephedrine has been reported to detect pheochromocytoma rapidly (within 2 to 5 minutes) and clearly in 9 of 10 patients, visualizing more lesions with better contrast than 131I-metaiodobenzylguanidine (92).
6-[18F]Fluorodopamine, a sympathoneural imaging agent developed at the NIH, is a positron-emitting analogue of dopamine and a good substrate for both the plasma membrane and intracellular vesicular transporters in catecholamine-synthesizing cells. This results in a tissue–blood concentration ratio for 6-[18F]fluorodopamine of more than 1000 and good visualization of pheochromocytoma tumor cells [100] Figure 3). In other types of cells, 6-[18F]fluorodopamine undergoes rapid metabolism and exit of the metabolites from the cells. Positron emission tomography using 18F-fluorodeoxyglucose is available for clinical diagnosis at several centers. 11C-hydroxyephedrine is used at the University of Michigan in Ann Arbor, and 6-[18F]fluorodopamine is used at the NIH.
|
The procedures we recommend for localization of pheochromocytoma are outlined in the imaging algorithm (Figure 4). Abdominal computed tomography or magnetic resonance imaging is done first, since both are relatively sensitive tests and have similar sensitivity and specificity in detecting adrenal pheochromocytoma (77). However, because of inadequate specificity, detection of a mass by these tests does not justify a diagnosis of pheochromocytoma. Thus, metaiodobenzylguanidine scanning is done for confirmation. If metaiodobenzylguanidine scanning is positive, the patient can go directly to surgery.
Negative results on metaiodobenzylguanidine scanning do not exclude a pheochromocytoma because the test has imperfect sensitivity. If results of abdominal computed tomography and magnetic resonance imaging are negative, then whole-body evaluation, usually by computed tomography or magnetic resonance imaging, is indicated; metaiodobenzylguanidine scanning results should also be reviewed with attention to the possibility of extra-adrenal pheochromocytoma. Continuous rotation or spiral computed tomography, with its high spatial resolution, is probably preferable here for detecting small thoracic tumors (101). Magnetic resonance imaging may be preferable for detection of juxtacardiac and juxtavascular pheochromocytoma (73).
Neither computed tomography nor magnetic resonance imaging has perfect sensitivity. Therefore, a patient may have a pheochromocytoma even if a mass is not detected by these imaging methods. We have begun to conduct 6-[18F]fluorodopamine positron emission tomography scanning in this setting. Alternative approaches include vena caval sampling for plasma catecholamines and metanephrines and clinical follow-up. At this time, 6-[18F]fluorodopamine positron emission tomography scanning is reserved for cases in which clinical symptoms and signs suggest pheochromocytoma and results of biochemical tests are positive, but conventional imaging studies cannot locate the tumor.
Management of Pheochromocytoma
|
|---|
Before the introduction of adrenergic blockade, pheochromocytoma surgical mortality rates ranged from 24% to 50% (103, 104). Routine preoperative pharmacologic blockade with phenoxybenzamine, an 
-adrenoceptor blocker, opposes catecholamine-induced vasoconstriction. A ß-adrenoceptor blocker is added to oppose the reflex tachycardia often associated with -blockade. ß-Blockade alone can be dangerous in patients with pheochromocytoma and is contraindicated in this setting because it does not prevent and can actually augment effects of catecholamines at -adrenoreceptors.
-Methyl- para-tyrosine (Merck Sharp & Dohme, West Point, Pennsylvania) competitively inhibits tyrosine hydroxylase, the rate-limiting step in catecholamine biosynthesis (103). Treatment with metyrosine reduces tumor stores of catecholamines, decreases the need for intraoperative medication to control blood pressure, lowers intraoperative fluid requirements, and attenuates blood loss (105). Depletion of tumor catecholamine stores also contributes to decreased ability of the tumor to react to stimulation. The combination of metyrosine, phenoxybenzamine, a ß-blocker, and liberal salt intake starting 10 to 14 days before surgery leads to better control of blood pressure and decreases surgical risks. Combined medical blockade also allows relaxation of the constricted vascular tree and expansion of the reduced plasma volume, thus avoiding shock after sudden diffuse vasodilation at the time of tumor removal. At midnight before surgery, the patient receives phenoxybenzamine and metyrosine and is assigned to bedrest to avoid orthostatic hypotension. Intravenous fluids are administered for hydration and to ensure adequate blood volume.
After adequate medical blockade and hydration, surgical excision of pheochromocytoma has been performed through a transabdominal incision, with palpation of the contralateral adrenal gland and sympathetic chain to identify possible additional tumors. Patient survival rates of 97.7% to 100% are usual after such procedures (104, 106-113). Residual nonparoxysmal hypertension is found in 27% to 38% of patients after tumor removal (107, 114, 115).
The recent development of laparoscopic surgical techniques has provided an alternative to open surgical procedures (116, 117). Advantages of laparoscopic surgery include less postoperative pain, shortened hospital stay and convalescent period, and improved cosmetic result. Both surgical approaches have similar blood loss and complications (118-126). Laparoscopic surgery is safe, has similar operative time, and shows no difference in blood pressure and heart rate increments when compared with open operations (123-127).
Patients with familial pheochromocytoma are predisposed to multiple or bilateral adrenal tumors. In our series, 64 patients developed 106 pheochromocytomas, of which 47% were bilateral adrenal and 21% were extra-adrenal. Evaluation of different families with von Hippel–Lindau disease has resulted in a clinical classification system (6, 33). Families without pheochromocytoma, classified as von Hippel–Lindau type 1, represent about 44% of von Hippel–Lindau disease families (36). von Hippel–Lindau families with pheochromocytoma (about 56% of von Hippel–Lindau families) are classified as von Hippel–Lindau type 2A or 2B, depending on the absence or presence of renal carcinoma.
Patients with MEN II, identified by screening, present at a younger age and with less frequent symptoms and hypertension (48%) than patients with sporadic pheochromocytoma (128). In contrast to small pheochromocytomas in von Hippel–Lindau disease, small pheochromocytomas in MEN II detected by screening are often functional; urinary catecholamine excretion is similar to that found in sporadic pheochromocytoma (128).
Pheochromocytomas occur in about 5% of patients with neurofibromatosis type 1 (129). Hypertension in patients with neurofibromatosis type 1 may be essential, renovascular, or, in 20% to 50% of cases, secondary to pheochromocytoma. Solitary adrenal tumors are most common; 9.7% of patients develop bilateral adrenal disease, and 6.3% of patients develop extra-adrenal pheochromocytoma.
Patients with pheochromocytoma secondary to von Hippel–Lindau disease present at a younger age and have fewer symptoms, less hypertension, and smaller and less functional tumors than patients with sporadic pheochromocytoma (6) (Table 3). Pheochromocytoma diagnosed without screening in patients with von Hippel–Lindau disease is associated with a higher incidence of symptoms and hypertension (130). This suggests that smaller, less functional tumors identified by screening account for "silent" pheochromocytomas in patients with von Hippel–Lindau disease (131).
|
Although adrenalectomy is the established treatment for sporadic pheochromocytoma, the treatment of hereditary forms of pheochromocytoma remains unsettled. Treatment has included follow-up observation of small nonfunctional pheochromocytomas, unilateral adrenalectomy for functional tumors, or prophylactic bilateral adrenalectomy.
Steroid "replacement" therapy after bilateral adrenalectomy often does not suffice for normalizing quality of life. Between 25% and 33% of patients undergoing bilateral adrenalectomy develop Addisonian crisis at some point, and attendant mortality rates are high (132, 133). Moreover, 30% of patients develop clinically significant fatigue, and 48% consider themselves handicapped (133).
In patients with pheochromocytoma, partial adrenalectomy can preserve adrenocortical function and avoid the morbidity of medical adrenal replacement (134, 135). Recently, laparoscopic partial adrenalectomy has been shown to provide clinical results similar to those seen with total adrenalectomy, with less surgical morbidity (103, 134). Although partial adrenalectomy can preserve adrenocortical function, these patients continue to be at risk for recurrent pheochromocytoma. Recurrent pheochromocytoma develops in 20% of patients with von Hippel–Lindau disease a median of 40 months after partial adrenalectomy (136). Patients with MEN II had up to a 33% risk for recurrent pheochromocytoma during 54 to 88 months of follow-up (137, 138). No complications or metastases have been reported secondary to recurrent pheochromocytoma in patients with von Hippel–Lindau disease or MEN II who had partial adrenalectomy (132, 135, 136, 138).
Postoperative follow-up of patients with sporadic and familial forms of pheochromocytoma includes evaluation of plasma metanephrine levels at approximately 6 weeks and again at 6 months after surgery. Because of the high rate of tumor recurrence in familial pheochromocytoma, we recommend yearly follow-up in these patients. Imaging studies should be performed on the basis of follow-up test results.
Future Trends in Diagnosis and Treatment of Pheochromocytoma
|
|---|
Regarding genetics, how do certain mutations predispose an individual to pheochromocytoma, and how do they lead to the different neurochemical and clinical phenotypes? Is there any identifiable marker for malignant potential or recurrence? Regarding diagnosis and localization, how can tests of plasma metanephrines be made more readily available? In prepaid medical systems, should these measurements be available systemwide to exclude pheochromocytoma, before other more complex, expensive tests are done? During follow-up of patients with positive biochemical test results, how can we more efficiently and cost-effectively distinguish false-positive from true-positive results? How does 6-[18F]fluorodopamine positron emission tomography compare with other less expensive and more readily available imaging agents for localization of pheochromocytoma? How can 123I-metaiodobenzylguanidine become more readily available in the United States? Regarding management, how can we improve the treatment of patients with sporadic, familial, recurrent, and malignant pheochromocytoma? Can pheochromocytoma be prevented in genetically predisposed patients?
Some of the above questions may be answered after identification of the specific molecular changes responsible for pheochromocytoma and the mechanisms linking identified germline or somatic genetic alterations to expression of specific tumor-cell phenotypes and clinical features of disease. New techniques, such as complementary DNA microarray analysis and laser-capture microdissection, offer tremendous potential for tracing phenotypic differences in tumors to underlying differences in gene expression and ultimately to the mutations responsible for the tumor. Such findings may lead to improved understanding of mechanisms of tumorigenesis, variations in the rate of disease progression, metastatic potential, tendency to recurrence, metabolic and hemodynamic alterations, variations in sensitivity and specificity of diagnostic tests, and development of and predicted responsiveness to novel treatments. For example, knowledge about expression of specific antigens or proteins, such as membrane catecholamine transporters, could lead to improvements in tumor imaging methods. It could also facilitate novel "magic bullet" therapy by targeting radionuclides, cytotoxins, or vaccines to tumor cells. This may be important, not only for treatment of malignant pheochromocytoma but also for prevention of pheochromocytoma in at-risk patients.
To move advances in disease diagnosis and treatment from the bench to the bedside, rigorous scientific proof of clinical efficacy and economic factors must be considered. The relative lack of availability of 123I-metaiodobenzylguanidine in the United States compared with other countries is one example of economic factors outweighing clinical benefits (85). Although pheochromocytoma is a rare tumor, its required consideration at a low pretest probability in large populations makes economic considerations important. To facilitate entry of assays of plasma metanephrines into the diagnostic mainstream, our assay methods are now available on line at www.catecholamine.org/labprocedures. Further advances, such as combining measurements of plasma metanephrines with more established diagnostic procedures (for example, the clonidine suppression test) offer further cost-effective potential for streamlining diagnostic decision making.
More generally, advances in the area of pheochromocytoma research and clinical practice can benefit from an interdisciplinary team approach, involving endocrinologists, clinical chemists, radiologists, nuclear medicine specialists, cardiologists, geneticists, pathologists, experts in basic molecular genetic analyses, and surgeons.
Author and Article Information
|
|---|
 Top Author & Article Info References |
|---|
An edited summary of a Clinical Staff Conference held on 29 September 1999 at the National Institutes of Health, Bethesda, Maryland.
Authors who wish to cite a section of the conference and specifically indicate its author may use this example for the form of the reference: Linehan WM, Walther MM.Molecular genetic abnormalities associated with pheochromocytoma. In: Pacak K, moderator. Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma. Ann Intern Med. 2001; 134:316-7.
Acknowledgment:The authors thank Drs. J.W.M. Lenders and B. Zbar for important contributions to the work presented at the Clinical Staff Conference.
Requests for Single Reprints:Karel Pacak, MD, PhD, DSc, Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 9D42, 10 Center Drive MSC-1583, Bethesda, MD 20892-1583; e-mail, karel{at}mail.nih.gov.
Current Author Addresses:Dr. Pacak: Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 9D42, 10 Center Drive MSC-1583, Bethesda, MD 20892-1583.
Drs. Linehan and Walther: Urologic Oncology Branch, National Cancer Institute, Building 10, Room 2B43, 10 Center Drive MSC-1501, Bethesda, MD 20892-1501.
Drs. Eisenhofer and Goldstein: Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 10, Room 6N252, 10 Center Drive MSC-1620, Bethesda, MD 20892-1620.
References
|
|---|
|
TopAuthor & Article InfoReferences |
|---|
1. Manger WM, Gifford RW Jr.Clinical and Experimental Pheochromocytoma. Cambridge, MA: Blackwell Science; 1996.
2. Mantero F, Terzolo M, Arnaldi G, Osella G, Masini AM, Ali A, et al. A survey on adrenal incidentaloma in Italy. Study Group on Adrenal Tumors of the Italian Society of Endocrinology J Clin Endocrinol Metab. 2000;85:637-44. [PMID: 0010690869].
3. Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, et al. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis JAMA. 1996;276:1575-9. [PMID: 0008918855].
4. Ponder BA. The phenotypes associated with ret mutations in the multiple endocrine neoplasia type 2 syndrome Cancer Res. 1999;59:1736s-1742s. [PMID: 0010197589].
5. Frank-Raue K, Hoppner W, Frilling A, Kotzerke J, Dralle H, Haase R, et al. Mutations of the ret protooncogene in German multiple endocrine neoplasia families: relation between genotype and phenotype. German Medullary Thyroid Carcinoma Study Group J Clin Endocrinol Metab. 1996;81:1780-3. [PMID: 0008626834].[Medline]
6. Walther MM, Reiter R, Keiser HR, Choyke PL, Venzon D, Hurley K, et al. Clinical and genetic characterization of pheochromocytoma in von Hippel–Lindau families: comparison with sporadic pheochromocytoma gives insight into natural history of pheochromocytoma J Urol. 1999;162:659-64. [PMID: 0010458336].[Medline]
7. Zbar B.Chromosomal deletions in lung cancer and renal cancer. In: DeVita VT, Hellman S, Rosenberg SA, eds. Important Advances in Oncology. Philadelphia: Lippincott; 1989.
8. Bos JL. ras oncogenes in human cancer: a review Cancer Res. 1989;49:4682-9. [PMID: 0002547513].[Medline]
9. Druker BJ, Mamon HJ, Roberts TM. Oncogenes, growth factors, and signal transduction N Engl J Med. 1989;321:1383-91. [PMID: 0002682241].[Medline]
10. Knudson AG. Antioncogenes and human cancer Proc Natl Acad Sci U S A. 1993;90:10914-21. [PMID: 0007902574].
11. Identification and characterization of the tuberous sclerosis gene on chromosome 16. The European Chromosome 16 Tuberous Sclerosis Consortium Cell. 1993;75:1305-15. [PMID: 0008269512].[Medline]
12. Cavenee WK, Hansen MF, Nordenskjold M, Kock E, Maumenee I, Squire JA, et al. Genetic origin of mutations predisposing to retinoblastoma Science. 1985;228:501-3. [PMID: 0003983638].
13. Cavenee WK, Murphree AL, Shull MM, Benedict WF, Sparkes RS, Kock E, et al. Prediction of familial predisposition to retinoblastoma N Engl J Med. 1986;314:1201-7. [PMID: 0003702916].[Medline]
14. Klein G. The approaching era of the tumor suppressor genes Science. 1987;238:1539-45. [PMID: 0003317834].
15. Dunn JM, Phillips RA, Becker AJ, Gallie BL. Identification of germline and somatic mutations affecting the retinoblastoma gene Science. 1988;241:1797-800. [PMID: 0003175621].
16. Kobayashi T, Hirayama Y, Kobayashi E, Kubo Y, Hino O. A germline insertion in the tuberous sclerosis (Tsc2) gene gives rise to the Eker rat model of dominantly inherited cancer Nat Genet. 1995;9:70-4. [PMID: 0007704028].
17. Schroeder WT, Chao LY, Dao DD, Strong LC, Pathak S, Riccardi V, et al. Nonrandom loss of maternal chromosome 11 alleles in Wilms tumors Am J Hum Genet. 1987;40:413-20. [PMID: 0002883892].[Medline]
18. Sager R. Tumor suppressor genes: the puzzle and the promise Science. 1989;246:1406-12. [PMID: 0002574499].
19. Francke U. Molecular genetics. A gene for Wilms tumour? Nature. 1990;343:692-4. [PMID: 0002154698].[Medline]
20. Donis-Keller H, Dou S, Chi D, Carlson KM, Toshima K, Lairmore TC, et al. Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC Hum Mol Genet. 1993;2:851-6. [PMID: 0008103403].[Medline]
21. Hofstra RM, Landsvater RM, Ceccherini I, Stulp RP, Stelwagen T, Luo Y, et al. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma Nature. 1994;367:375-6. [PMID: 0007906866].[Medline]
22. Hopkin K. One gene, four syndromes: the story of RET Journal of National Institutes of Health Research. 1994;6:33-5.
23. Marsh DJ, Andrew SD, Eng C, Learoyd DL, Capes AG, Pojer R, et al. Germline and somatic mutations in an oncogene: RET mutations in inherited medullary thyroid carcinoma Cancer Res. 1996;56:1241-3. [PMID: 0008640806].[Medline]
24. Mulligan LM, Kwok JB, Healey CS, Elsdon MJ, Eng C, Gardner E, et al. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A Nature. 1993;363:458-60. [PMID: 0008099202].[Medline]
25. Mulligan LM, Eng C, Healey CS, Clayton D, Kwok JB, Gardner E, et al. Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC Nat Genet. 1994;6:70-4. [PMID: 0007907913].
26. Raue F. German medullary thyroid carcinoma/multiple endocrine neoplasia registry. German MTC/MEN Study Group. Medullary Thyroid Carcinoma/Multiple Endocrine Neoplasia Type 2 Langenbecks Arch Surg. 1998;383:334-6. [PMID: 0009860226].[Medline]
27. Eng C, Thomas GA, Neuberg DS, Mulligan LM, Healey CS, Houghton C, et al. Mutation of the RET proto-oncogene is correlated with RET immunostaining in subpopulations of cells in sporadic medullary thyroid carcinoma J Clin Endocrinol Metab. 1998;83:4310-3. [PMID: 0009851769].[Medline]
28. Latif F, Duh FM, Gnarra J, Tory K, Kuzmin I, Yao M, et al. von Hippel–Lindau syndrome: cloning and identification of the plasma membrane Ca(++)-transporting ATPase isoform 2 gene that resides in the von Hippel–Lindau gene region Cancer Res. 1993;53:861-7. [PMID: 0008428366].[Medline]
29. Glenn GM, Choyke PL, Zbar B, Linehan WM.Von Hippel–Lindau disease: clinical review and molecular genetics. In: Anderson EE, ed. Problems in Urologic Surgery: Benign and Malignant Tumors of the Kidney. Philadelphia: Lippincott; 1990: 312-30.
30. Linehan WM, Lerman MI, Zbar B. Identification of the von Hippel–Lindau (VHL) gene. Its role in renal cancer JAMA. 1995;273:564-70. [PMID: 0007837390].
31. Linehan WM, Klausner RD.Renal carcinoma. In: Vogelstein B, Kinzler KW, eds. The Genetic Basis of Human Cancer. New York: McGraw-Hill; 1998:455-73.
32. Brauch H, Kishida T, Glavac D, Chen F, Pausch F, Hofler H, et al. Von Hippel–Lindau (VHL) disease with pheochromocytoma in the Black Forest region of Germany: evidence for a founder effect Hum Genet. 1995;95:551-6. [PMID: 0007759077].[Medline]
33. Chen F, Kishida T, Yao M, Hustad T, Glavac D, Dean M, et al. Germline mutations in the von Hippel–Lindau disease tumor suppressor gene: correlations with phenotype Hum Mutat. 1995;5:66-75. [PMID: 0007728151].[Medline]
34. Tisherman SE, Tisherman BG, Tisherman SA, Dunmire S, Levey GS, Mulvihill JJ. Three-decade investigation of familial pheochromocytoma. An allele of von Hippel–Lindau disease? Arch Intern Med. 1993;153:2550-6. [PMID: 0008239848].[Medline]
35. Crossey PA, Eng C, Ginalska-Malinowska M, Lennard TW, Wheeler DC, Ponder BA, et al. Molecular genetic diagnosis of von Hippel–Lindau disease in familial phaeochromocytoma J Med Genet. 1995;32:885-6. [PMID: 0008592333].[Medline]
36. Chen F, Slife L, Kishida T, Mulvihill J, Tisherman SE, Zbar B. Genotype-phenotype correlation in von Hippel–Lindau disease: identification of a mutation associated with VHL type 2A J Med Genet. 1996;33:716-7. [PMID: 0008863170].[Medline]
37. Gross DJ, Avishai N, Meiner V, Filon D, Zbar B, Abeliovich D. Familial pheochromocytoma associated with a novel mutation in the von Hippel–Lindau gene J Clin Endocrinol Metab. 1996;81:147-9. [PMID: 0008550742].
38. Maddock IR, Moran A, Maher ER, Teare MD, Norman A, Payne SJ, et al. A genetic register for von Hippel–Lindau disease J Med Genet. 1996;33:120-7. [PMID: 0008929948].[Medline]
39. Stuhrmann M.Genetic changes associated with MEN2A. In: Muller H, Scott RJ, Weber W, eds. Hereditary Cancer. Second International Research Conference on Familial Cancer. Basel, Switzerland: Karger; 1996:99-101.
40. Neumann HP, Eng C, Mulligan LM, Glavac D, Zauner I, Ponder BA, et al. Consequences of direct genetic testing for germline mutations in the clinical management of families with multiple endocrine neoplasia, type II JAMA. 1995;274:1149-51. [PMID: 0007563486].
41. Walther MM, Linehan WM. Von Hippel–Lindau disease and pheochromocytoma [Letter] JAMA. 1996;275:839-40. [PMID: 0008596219].
42. Stolle C, Glenn G, Zbar B, Humphrey JS, Choyke P, Walther M, et al. Improved detection of germline mutations in the von Hippel–Lindau disease tumor suppressor gene Hum Mutat. 1998;12:417-23. [PMID: 0009829911].
43. Eng C. Seminars in medicine of the Beth Israel Hospital, Boston. The RET proto-oncogene in multiple endocrine neoplasia type 2 and Hirschsprung's disease N Engl J Med. 1996;335:943-51. [PMID: 0008782503].
44. Howe JR, Norton JA, Wells SA Jr. Prevalence of pheochromocytoma and hyperparathyroidism in multiple endocrine neoplasia type 2A: results of long-term follow-up Surgery. 1993;114:1070-7. [PMID: 0007903003].[Medline]
45. Shawar L, Svec F. Pheochromocytoma with elevated metanephrines as the only biochemical finding J La State Med Soc. 1996;148:535-8. [PMID: 0008990798].[Medline]
46. Lenders JW, Keiser HR, Goldstein DS, Willemsen JJ, Friberg P, Jacobs MC, et al. Plasma metanephrines in the diagnosis of pheochromocytoma Ann Intern Med. 1995;123:101-9. [PMID: 0007778821].
47. Gerlo EA, Sevens C. Urinary and plasma catecholamines and urinary catecholamine metabolites in pheochromocytoma: diagnostic value in 19 cases Clin Chem. 1994;40:250-6. [PMID: 0007906208].[Medline]
48. Bravo EL, Tarazi RC, Gifford RW, Stewart BH. Circulating and urinary catecholamines in pheochromocytoma. Diagnostic and pathophysiologic implications N Engl J Med. 1979;301:682-6. [PMID: 0000481462].[Medline]
49. Bravo EL. Evolving concepts in the pathophysiology, diagnosis, and treatment of pheochromocytoma Endocr Rev. 1994;15:356-68. [PMID: 0008076587].
50. Sinclair D, Shenkin A, Lorimer AR. Normal catecholamine production in a patient with a paroxysmally secreting phaeochromocytoma Ann Clin Biochem. 1991;28:417-9. [PMID: 0001892355].[Medline]
51. Stewart MF, Reed P, Weinkove C, Moriarty KJ, Ralston AJ. Biochemical diagnosis of phaeochromocytoma: two instructive case reports J Clin Pathol. 1993;46:280-2. [PMID: 0008463426].[Medline]
52. Hsiao RJ, Neumann HP, Parmer RJ, Barbosa JA, O'Connor DT. Chromogranin A in familial pheochromocytoma: diagnostic screening value, prediction of tumor mass, and post-resection kinetics indicating two-compartment distribution Am J Med. 1990;88:607-13. [PMID: 0002189303].
53. Hsiao RJ, Parmer RJ, Takiyyuddin MA, O'Connor DT. Chromogranin A storage and secretion: sensitivity and specificity for the diagnosis of pheochromocytoma Medicine Baltimore. 1991;70:33-45. [PMID: 0001988765].[Medline]
54. Canale MP, Bravo EL. Diagnostic specificity of serum chromogranin-A for pheochromocytoma in patients with renal dysfunction J Clin Endocrinol Metab. 1994;78:1139-44. [PMID: 0008175970].[Medline]
55. Boomsma F, Bhaggoe UM, Man in 't Veld AJ, Schalekamp MA. Sensitivity and specificity of a new ELISA method for determination of chromogranin A in the diagnosis of pheochromocytoma and neuroblastoma Clin Chim Acta. 1995;239:57-63. [PMID: 0007586587].[Medline]
56. Eisenhofer G, Lenders JW, Linehan WM, Walther MM, Goldstein DS, Keiser HR. Plasma normetanephrine and metanephrine for detecting pheochromocytoma in von Hippel–Lindau disease and multiple endocrine neoplasia type 2 N Engl J Med. 1999;340:1872-9. [PMID: 0010369850].
57. Raber W, Raffesberg W, Kmen E, Hamus A, Niedarle B, Waldhause W, et al. Pheochromocytoma with normal urinary and plasma catecholamines but elevated plasma free metanephrines in a patient with adrenal incidentaloma Endocrinologist. 2000;10:65-8.
58. Goldstein DS.Stress, Catecholamines, and Cardiovascular Disease. New York: Oxford Univ Pr; 1995.
59. Goodman SN. Toward evidence-based medical statistics. 2: The Bayes factor Ann Intern Med. 1999;130:1005-13. [PMID: 0010383350].[Medline]
60. Davidoff F. Standing statistics right side up [Editorial] Ann Intern Med. 1999;130:1019-21. [PMID: 0010383353].[Medline]
61. Sjoberg RJ, Simcic KJ, Kidd GS. The clonidine suppression test for pheochromocytoma. A review of its utility and pitfalls Arch Intern Med. 1992;152:1193-7. [PMID: 0001599347].[Medline]
62. Koshida H, Miyamori I, Soma R, Matsubara T, Okamoto S, Ikeda M, et al. Evaluation of clonidine suppression and various provocation tests in the diagnosis of pheochromocytoma J Endocrinol Invest. 1990;13:807-15. [PMID: 0002096157].[Medline]
63. Taylor HC, Mayes D, Anton AH. Clonidine suppression test for pheochromocytoma: examples of misleading results J Clin Endocrinol Metab. 1986;63:238-42. [PMID: 0003711261].[Medline]
64. Bravo EL, Tarazi RC, Fouad FM, Vidt DG, Gifford RW Jr. Clonidine-suppression test: a useful aid in the diagnosis of pheochromocytoma N Engl J Med. 1981;305:623-6. [PMID: 0007266587].[Medline]
65. Mannelli M, De Feo ML, Maggi M, Pupilli C, Opocher G, Valenza T, et al. Usefulness of basal catecholamine plasma levels and clonidine suppression test in the diagnosis of pheochromocytoma J Endocrinol Invest. 1987;10:377-82. [PMID: 0002890684].[Medline]
66. Lenz T, Ross A, Schumm-Draeger P, Schulte KL, Geiger H. Clonidine suppression test revisited Blood Press. 1998;7:153-9. [PMID: 0009758085].[Medline]
67. Karlberg BE, Hedman L. Value of the clonidine suppression test in the diagnosis of pheochromocytoma Acta Med Scand Suppl. 1986;714:15-21. [PMID: 0003472437].[Medline]
68. Elliott WJ, Murphy MB. Reduced specificity of the clonidine suppression test in patients with normal plasma catecholamine levels Am J Med. 1988;84:419-24. [PMID: 0003348244].[Medline]
69. Hui TP, Krakoff LR, Felton K, Yeager K. Diuretic treatment alters clonidine suppression of plasma norepinephrine Hypertension. 1986;8:272-6. [PMID: 0003514447].[Medline]
70. Grossman E, Goldstein DS, Hoffman A, Keiser HR. Glucagon and clonidine testing in the diagnosis of pheochromocytoma Hypertension. 1991;17:733-41. [PMID: 0002045133].[Medline]
71. Bravo EL, Gifford RW Jr. Current concepts. Pheochromocytoma: diagnosis, localization and management N Engl J Med. 1984;311:1298-303. [PMID: 0006149463].[Medline]
72. Goldstein RE, O'Neill JA Jr, Holcomb GW 3rd, Morgan WM 3rd, Neblett WW 3rd, Oates JA, et al. Clinical experience over 48 years with pheochromocytoma Ann Surg. 1999;229:755-66. [PMID: 0010363888].
73. Francis IR, Korobkin M. Pheochromocytoma Radiol Clin North Am. 1996;34:1101-12. [PMID: 0008898786].[Medline]
74. Maurea S, Cuocolo A, Reynolds JC, Tumeh SS, Begley MG, Linehan WM, et al. Iodine-131-metaiodobenzylguanidine scintigraphy in preoperative and postoperative evaluation of paragangliomas: comparison with CT and MRI J Nucl Med. 1993;34:173-9. [PMID: 0008381474].[Medline]
75. Quint LE, Glazer GM, Francis IR, Shapiro B, Chenevert TL. Pheochromocytoma and paraganglioma: comparison of MR imaging with CT and I-131 MIBG scintigraphy Radiology. 1987;165:89-93. [PMID: 0003628794].[Medline]
76. Mannelli M, Ianni L, Cilotti A, Conti A. Pheochromocytoma in Italy: a multicentric retrospective study Eur J Endocrinol. 1999;141:619-24. [PMID: 0010601965].
77. Maurea S, Cuocolo A, Reynolds JC, Neumann RD, Salvatore M. Diagnostic imaging in patients with paragangliomas. Computed tomography, magnetic resonance and MIBG scintigraphy comparison Q J Nucl Med. 1996;40:365-71. [PMID: 0009050342].[Medline]
78. Sisson JC, Shulkin BL. Nuclear medicine imaging of pheochromocytoma and neuroblastoma Q J Nucl Med. 1999;43:217-23. [PMID: 0010568137].[Medline]
79. Sisson JC, Frager MS, Valk TW, Gross MD, Swanson DP, Wieland DM, et al. Scintigraphic localization of pheochromocytoma N Engl J Med. 1981;305:12-7. [PMID: 0007231514].[Medline]
80. Shapiro B, Sisson JC, Shulkin BL, Gross MD, Zempel S. The current status of meta-iodobenzylguanidine and related agents for the diagnosis of neuro-endocrine tumors Q J Nucl Med. 1995;39:3-8. [PMID: 0009002740].
81. Swensen SJ, Brown ML, Sheps SG, Sizemore GW, Gharib H, Grant CS, et al. Use of 131I-MIBG scintigraphy in the evaluation of suspected pheochromocytoma Mayo Clin Proc. 1985;60:299-304. [PMID: 0003990377].[Medline]
82. Ackery DM, Tippett PA, Condon BR, Sutton HE, Wyeth P. New approach to the localisation of phaeochromocytoma: imaging with iodine-131-meta-iodobenzylguanidine Br Med J Clin Res Ed. 1984;288:1587-91. [PMID: 0006426655].[Medline]
83. Campeau RJ, Garcia OM, Correa OA, Rege AB. Pheochromocytoma: diagnosis by scintigraphy using iodine 131 metaiodobenzylguanidine South Med J. 1991;84:1221-30. [PMID: 0001925724].[Medline]
84. Baulieu J, Guilloteau C, Canbon C. MIBG scintigraphy: a one-year experience J Nucl Med. 1984;25:111.
85. Eisenhofer G, Pacak K, Goldstein DS, Chen C, Shulkin B. 123I-MIBG scintigraphy of catecholamine systems: impediments to applications in clinical medicine [Letter] Eur J Nucl Med. 2000;27:611-2. [PMID: 0010853820].[Medline]
86. Tsuchimochi S, Nakajo M, Nakabeppu Y, Tani A. Metastatic pulmonary pheochromocytomas: positive I-123 MIBG SPECT with negative I-131 MIBG and equivocal I-123 MIBG planar imaging Clin Nucl Med. 1997;22:687-90. [PMID: 0009343724].
87. Shulkin BL, Shapiro B, Francis IR, Dorr R, Shen SW, Sisson JC. Primary extra-adrenal pheochromocytoma: positive I-123 MIBG imaging with negative I-131 MIBG imaging Clin Nucl Med. 1986;11:851-4. [PMID: 0003815982].[Medline]
88. Lynn MD, Shapiro B, Sisson JC, Beierwaltes WH, Meyers LJ, Ackerman R, et al. Pheochromocytoma and the normal adrenal medulla: improved visualization with I-123 MIBG scintigraphy Radiology. 1985;155:789-92. [PMID: 0004001380].[Medline]
89. Tewson TJ, Krohn KA. PET radiopharmaceuticals: state-of-the-art and future prospects Semin Nucl Med. 1998;28:221-34. [PMID: 0009704364].[Medline]
90. Urbain JL, Vekemans MC, Lemieux SK, Cosenza SC, Senadhi VK, Milestone BN, et al. Nuclear oncology and the Imagene concept Acta Radiol Suppl. 1997;412:21-8. [PMID: 0009240077].[Medline]
91. Shulkin BL, Thompson NW, Shapiro B, Francis IR, Sisson JC. Pheochromocytomas: imaging with 2-deoxy-D-glucose PET Radiology. 1999;212:35-41. [PMID: 0010405717].[Medline]
92. Shulkin BL, Wieland DM, Schwaiger M, Thompson NW, Francis IR, Haka MS, et al. PET scanning with hydroxyephedrine: an approach to the localization of pheochromocytoma J Nucl Med. 1992;33:1125-31. [PMID: 0001597727].[Medline]
93. Scott WJ, Schwabe JL, Gupta NC, Dewan NA, Reeb SD, Sugimoto JT. Positron emission tomography of lung tumors and mediastinal lymph nodes using Ann Thorac Surg. 1994;58:698-703. [PMID: 0007944691].[Medline]
94. Strauss LG, Conti PS. The applications of PET in clinical oncology J Nucl Med. 1991;32:623-50. [PMID: 0002013803].[Medline]
95. Adams S, Baum R, Rink T, Schumm-Drager PM, Usadel KH, Hor G. Limited value of fluorine-18 fluorodeoxyglucose positron emission tomography for the imaging of neuroendocrine tumours Eur J Nucl Med. 1998;25:79-83. [PMID: 0009396878].
96. Duhaylongsod FG, Lowe VJ, Patz EF Jr, Vaughn AL, Coleman RE, Wolfe WG. Lung tumor growth correlates with glucose metabolism measured by fluoride-18 fluorodeoxyglucose positron emission tomography Ann Thorac Surg. 1995;60:1348-52. [PMID: 0008526625].
97. Shulkin B. PET epinephrine studies of pheochromocytoma J Nucl Med. 1995;36:22P-23P.
98. Neumann DR, Basile KE, Bravo EL, Chen EQ, Go RT. Malignant pheochromocytoma of the anterior mediastinum: PET findings with [18F]FGD and B2Rb J Comput Assist Tomogr. 1996;20:312-6. [PMID: 0008606245].[Medline]
99. Musholt TJ, Musholt PB, Dehdashti F, Moley JF. Evaluation of fluorodeoxyglucose-positron emission tomographic scanning and its association with glucose transporter expression in medullary thyroid carcinoma and pheochromocytoma: a clinical and molecular study Surgery. 1997;122:1049-61. [PMID: 0009426419].[Medline]
100. Hovevey-Sion D, Eisenhofer G, Kopin IJ, Kirk KL, Chang PC, Szemeredi K, et al. Metabolic fate of injected radiolabelled dopamine and 2-fluorodopamine in rats Neuropharmacology. 1990;29:881-7. [PMID: 0002255383].[Medline]
101. Chatal JF. Can we agree on the best imaging procedure(s) for localization of pheochromocytomas? [Editorial] J Nucl Med. 1993;34:180-1. [PMID: 0008429333].[Medline]
102. Walther MM, Keiser HR, Linehan WM. Pheochromocytoma: evaluation, diagnosis, and treatment World J Urol. 1999;17:35-9. [PMID: 0010096149].
103. Pullerits J, Ein S, Balfe JW. Anaesthesia for phaeochromocytoma Can J Anaesth. 1988;35:526-34. [PMID: 0003048757].[Medline]
104. Levine SN, McDonald JC. The evaluation and management of pheochromocytomas Adv Surg. 1984;17:281-313. [PMID: 0006367394].
105. Perry RR, Keiser HR, Norton JA, Wall RT, Robertson CN, Travis W, et al. Surgical management of pheochromocytoma with the use of metyrosine Ann Surg. 1990;212:621-8. [PMID: 0001978640].[Medline]
106. Modlin IM, Farndon JR, Shepherd A, Johnston ID, Kennedy TL, Montgomery DA, et al. Phaeochromocytomas in 72 patients: clinical and diagnostic features, treatment and long term results Br J Surg. 1979;66:456-65. [PMID: 0000466037].[Medline]
107. Remine WH, Chong GC, Van Heerden JA, Sheps SG, Harrison EG Jr. Current management of pheochromocytoma Ann Surg. 1974;179:740-8. [PMID: 0004823849].[Medline]
108. Favia G, Lumachi F, Polistina F, D'Amico DF. Pheochromocytoma, a rare cause of hypertension: long-term follow-up of 55 surgically treated patients World J Surg. 1998;22:689-94. [PMID: 0009606283].
109. Beatty OL, Russell CF, Kennedy L, Hadden DR, Kennedy TL, Atkinson AB. Phaeochromocytoma in Northern Ireland: a 21 year review Eur J Surg. 1996;162:695-702. [PMID: 0008908450].[Medline]
110. Obara T, Kanbe M, Okamoto T, Ito Y, Yamashita T, Ito K, et al. Surgical strategy for pheochromocytoma: emphasis on the pledge of flank extraperitoneal approach in selected patients Surgery. 1995;118:1083-9. [PMID: 0007491527].[Medline]
111. Nagesser SK, Kievit J, Hermans J, Krans HM, van de Velde CJ. The surgical approach to the adrenal gland: a comparison of the retroperitoneal and the transabdominal routes in 326 operations on 284 patients Jpn J Clin Oncol. 2000;30:68-74. [PMID: 0010768869].
112. Lucon AM, Pereira MA, Mendonca BB, Halpern A, Wajchenbeg BL, Arap S. Pheochromocytoma: study of 50 cases J Urol. 1997;157:1208-12. [PMID: 0009120903].
113. de Graaf JS, Dullaart RP, Zwierstra RP. Complications after bilateral adrenalectomy for phaeochromocytoma in multiple endocrine neoplasia type 2—a plea to conserve adrenal function Eur J Surg. 1999;165:843-6. [PMID: 0010533758].
114. Shapiro B, Fig LM. Management of pheochromocytoma Endocrinol Metab Clin North Am. 1989;18:443-81. [PMID: 0002663482].[Medline]
115. Ellison GT, Mansberger JA, Mansberger AR Jr. Malignant recurrent pheochromocytoma during pregnancy: case report and review of the literature Surgery. 1988;103:484-9. [PMID: 0003281301].[Medline]
116. Orchard T, Grant CS, van Heerden JA, Weaver A. Pheochromocytoma—continuing evolution of surgical therapy Surgery. 1993;114:1153-9. [PMID: 0008256222].[Medline]
117. Pattou FN, Combemale FP, Poirette JF, Carnaille B, Wemeau JL, Huglo D, et al. Questionability of the benefits of routine laparotomy as the surgical approach for pheochromocytomas and abdominal paragangliomas Surgery. 1996;120:1006-12. [PMID: 0008957487].[Medline]
118. Thompson GB, Grant CS, van Heerden JA, Schlinkert RT, Young WF Jr, Farley DR, et al. Laparoscopic versus open posterior adrenalectomy: a case–control study of 100 patients Surgery. 1997;122:1132-6. [PMID: 0009426429].[Medline]
119. Staren ED, Prinz RA. Adrenalectomy in the era of laparoscopy Surgery. 1996;120:706-11. [PMID: 0008862381].
120. Brunt LM, Doherty GM, Norton JA, Soper NJ, Quasebarth MA, Moley JF. Laparoscopic adrenalectomy compared to open adrenalectomy for benign adrenal neoplasms J Am Coll Surg. 1996;183:1-10. [PMID: 0008673301].[Medline]
121. Aldrighetti L, Giacomelli M, Calori G, Paganelli M, Ferla G. Impact of minimally invasive surgery on adrenalectomy for incidental tumors: comparison with laparotomic technique Int Surg. 1997;82:160-4. [PMID: 0009331845].[Medline]
122. Gagner M, Pomp A, Heniford BT, Pharand D, Lacroix A. Laparoscopic adrenalectomy: lessons learned from 100 consecutive procedures Ann Surg. 1997;226:238-47. [PMID: 0009339930].
123. Guazzoni G, Montorsi F, Bocciardi A, Da Pozzo L, Rigatti P, Lanzi R, et al. Transperitoneal laparoscopic versus open adrenalectomy for benign hyperfunctioning adrenal tumors: a comparative study J Urol. 1995;153:1597-600. [PMID: 0007714980].[Medline]
124. Reinig JW, Doppman JL, Dwyer AJ, Johnson AR, Knop RH. Adrenal masses differentiated by MR Radiology. 1986;158:81-4. [PMID: 0003940403].[Medline]
125. Vargas HI, Kavoussi LR, Bartlett DL, Wagner JR, Venzon DJ, Fraker DL, et al. Laparoscopic adrenalectomy: a new standard of care Urology. 1997;49:673-8. [PMID: 0009145969].[Medline]
126. Linos DA, Stylopoulos N, Boukis M, Souvatzoglou A, Raptis S, Papadimitriou J. Anterior, posterior, or laparoscopic approach for the management of adrenal diseases? Am J Surg. 1997;173:120-5. [PMID: 0009074377].[Medline]
127. Gagner M, Breton G, Pharand D, Pomp A. Is laparoscopic adrenalectomy indicated for pheochromocytomas? Surgery. 1996;120:1076-80. [PMID: 0008957498].[Medline]
128. Pomares FJ, Canas R, Rodriguez JM, Hernandez AM, Parrilla P, Tebar FJ. Differences between sporadic and multiple endocrine neoplasia type 2A phaeochromocytoma Clin Endocrinol Oxf. 1998;48:195-200. [PMID: 0009579232].[Medline]
129. Walther MM, Herring J, Enquist E, Keiser HR, Linehan WM. von Recklinghausen's disease and pheochromocytomas J Urol. 1999;162:1582-6. [PMID: 0010524872].
130. Richard S, Beigelman C, Duclos JM, Fendler JP, Plauchu H, Plouin PF, et al. Pheochromocytoma as the first manifestation of von Hippel–Lindau disease Surgery. 1994;116:1076-81. [PMID: 0007985090].[Medline]
131. Aprill BS, Drake AJ 3rd, Lasseter DH, Shakir KM. Silent adrenal nodules in von Hippel–Lindau disease suggest pheochromocytoma Ann Intern Med. 1994;120:485-7. [PMID: 0008311371].[Medline]
132. Lairmore TC, Ball DW, Baylin SB, Wells SA Jr. Management of pheochromocytomas in patients with multiple endocrine neoplasia type 2 syndromes Ann Surg. 1993;217:595-603. [PMID: 0008099474].[Medline]
133. Telenius-Berg M, Ponder MA, Berg B, Ponder BA, Werner S. Quality of life after bilateral adrenalectomy in MEN 2 Henry Ford Hosp Med J. 1989;37:160-3. [PMID: 0002576954].[Medline]
134. Walther MM, Keiser HR, Choyke PL, Rayford W, Lyne JC, Linehan WM. Management of hereditary pheochromocytoma in von Hippel–Lindau kindreds with partial adrenalectomy J Urol. 1999;161:395-8. [PMID: 0009915410].
135. Lee JE, Curley SA, Gagel RF, Evans DB, Hickey RC. Cortical-sparing adrenalectomy for patients with bilateral pheochromocytoma Surgery. 1996;120:1064-71. [PMID: 0008957496].
136. Walther MM, Herring J, Choyke PL, Linehan WM. Laparoscopic partial adrenalectomy in patients with hereditary forms of pheochromocytoma J Urol. 2000;164:14-7. [PMID: 0010840414].
137. Okamoto T, Obara T, Ito Y, Yamashita T, Kanbe M, Iihara M, et al. Bilateral adrenalectomy with autotransplantation of adrenocortical tissue or unilateral adrenalectomy: treatment options for pheochromocytomas in multiple endocrine neoplasia type 2A Endocr J. 1996;43:169-75. [PMID: 0008793332].[Medline]
138. Albanese CT, Wiener ES. Routine total bilateral adrenalectomy is not warranted in childhood familial pheochromocytoma J Pediatr Surg. 1993;28:1248-52. [PMID: 0008263682].[Medline]
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Facebook 
Reddit 
Technorati 
Twitter What's this?
Related articles in Annals:
This article has been cited by other articles:
|
|
 |
|
  A. A. Malik, A. E. Houni, H. Gulshad, S. Elsiah, and S. Al-Salam An interesting case of paraganglioma BMJ Case Reports, May 25, 2009; 2009(may25_1): bcr1020081150 - bcr1020081150. [Full Text]
|
|
|
|
 |
|
 H Kahal, E Cooper, R Sriraman, and D V Coppini A woman with a suprarenal mass and hypertension BMJ, March 4, 2009; 338(mar04_2): b333 - b333. [Full Text]
|
|
|
|
 |
|
 I. Ilias, C. C. Chen, J. A. Carrasquillo, M. Whatley, A. Ling, I. Lazurova, K. T. Adams, S. Perera, and K. Pacak Comparison of 6-18F-Fluorodopamine PET with 123I-Metaiodobenzylguanidine and 111In-Pentetreotide Scintigraphy in Localization of Nonmetastatic and Metastatic Pheochromocytoma J. Nucl. Med., October 1, 2008; 49(10): 1613 - 1619. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R Armstrong, M Sridhar, K L Greenhalgh, L Howell, C Jones, C Landes, J L McPartland, C Moores, P D Losty, and M Didi Phaeochromocytoma in children Arch. Dis. Child., October 1, 2008; 93(10): 899 - 904. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. T. Adler, G. Y. Meyer-Rochow, H. Chen, D. E. Benn, B. G. Robinson, R. S. Sippel, and S. B. Sidhu Pheochromocytoma: Current Approaches and Future Directions Oncologist, July 1, 2008; 13(7): 779 - 793. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Karagiannis, D. P Mikhailidis, V. G Athyros, and F. Harsoulis Pheochromocytoma: an update on genetics and management Endocr. Relat. Cancer, December 1, 2007; 14(4): 935 - 956. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Pacak Preoperative Management of the Pheochromocytoma Patient J. Clin. Endocrinol. Metab., November 1, 2007; 92(11): 4069 - 4079. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Chrisoulidou, G. Kaltsas, I. Ilias, and A. B Grossman The diagnosis and management of malignant phaeochromocytoma and paraganglioma Endocr. Relat. Cancer, September 1, 2007; 14(3): 569 - 585. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. L. Brain, J. Kay, and B. Shine Measurement of Urinary Metanephrines to Screen for Pheochromocytoma in an Unselected Hospital Referral Population Clin. Chem., November 1, 2006; 52(11): 2060 - 2064. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. W. Bowen, J. Civan, A. Orlin, and T. Gleason Management of Type A Aortic Dissection and a Large Pheochromocytoma: A Surgical Dilemma Ann. Thorac. Surg., June 1, 2006; 81(6): 2296 - 2298. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Sullivan, T. Groshong, and J. D. Tobias Presenting Signs and Symptoms of Pheochromocytoma in Pediatric-aged Patients Clinical Pediatrics, October 1, 2005; 44(8): 715 - 719. [Abstract] [PDF]
|
|
|
|
|
|
R Nawar and D Aron Adrenal incidentalomas -- a continuing management dilemma Endocr. Relat. Cancer, September 1, 2005; 12(3): 585 - 598. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Marx and W. F. Simonds Hereditary Hormone Excess: Genes, Molecular Pathways, and Syndromes Endocr. Rev., August 1, 2005; 26(5): 615 - 661. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Kantorovich and K. Pacak A New Concept of Unopposed {beta}-Adrenergic Overstimulation in a Patient with Pheochromocytoma Ann Intern Med, June 21, 2005; 142(12_Part_1): 1026 - 1028. [Full Text] [PDF]
|
|
|
|
|
|
F M Brouwers, E F Petricoin III, L Ksinantova, J Breza, V Rajapakse, S Ross, D Johann, M Mannelli, B L Shulkin, R Kvetnansky, et al. Low molecular weight proteomic information distinguishes metastatic from benign pheochromocytoma Endocr. Relat. Cancer, June 1, 2005; 12(2): 263 - 272. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. W. A. Vogel, F. M. Brouwers, I. A. Lubensky, A. O. Vortmeyer, R. J. Weil, M. M. Walther, E. H. Oldfield, W. M. Linehan, K. Pacak, and Z. Zhuang Differential Expression of Erythropoietin and Its Receptor in von Hippel-Lindau-Associated and Multiple Endocrine Neoplasia Type 2-Associated Pheochromocytomas J. Clin. Endocrinol. Metab., June 1, 2005; 90(6): 3747 - 3751. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Amar, A. Servais, A.-P. Gimenez-Roqueplo, F. Zinzindohoue, G. Chatellier, and P.-F. Plouin Year of Diagnosis, Features at Presentation, and Risk of Recurrence in Patients with Pheochromocytoma or Secreting Paraganglioma J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2110 - 2116. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. E. Garber and K. Offit Hereditary Cancer Predisposition Syndromes J. Clin. Oncol., January 10, 2005; 23(2): 276 - 292. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Brown, P. A. Goldberg, J. G. Selter, H. S. Cabin, N. J. Marieb, R. Udelsman, and J. F. Setaro Hemorrhagic Pheochromocytoma Associated with Systemic Corticosteroid Therapy and Presenting as Myocardial Infarction with Severe Hypertension J. Clin. Endocrinol. Metab., January 1, 2005; 90(1): 563 - 569. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Pacak, G. Eisenhofer, and D. S. Goldstein Functional Imaging of Endocrine Tumors: Role of Positron Emission Tomography Endocr. Rev., August 1, 2004; 25(4): 568 - 580. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. A. Kaltsas, G. M. Besser, and A. B. Grossman The Diagnosis and Medical Management of Advanced Neuroendocrine Tumors Endocr. Rev., June 1, 2004; 25(3): 458 - 511. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Sawka, A. Gafni, L. Thabane, and W. F. Young Jr. The Economic Implications of Three Biochemical Screening Algorithms for Pheochromocytoma J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2859 - 2866. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Mansmann, J. Lau, E. Balk, M. Rothberg, Y. Miyachi, and S. R. Bornstein The Clinically Inapparent Adrenal Mass: Update in Diagnosis and Management Endocr. Rev., April 1, 2004; 25(2): 309 - 340. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. D. Garovic, M. C. Hogan, S. K. R. Kanakiriya, C. S. Grant, and W. F. Young Jr Labile hypertension, increased metanephrines and imaging misadventures Nephrol. Dial. Transplant., April 1, 2004; 19(4): 1004 - 1006. [Full Text] [PDF]
|
|
|
|
|
|
L Zendron, J Fehrenbach, C Taverna, and M Krause Pitfalls in the diagnosis of phaeochromocytoma BMJ, March 13, 2004; 328(7440): 629 - 630. [Full Text] [PDF]
|
|
|
|
|
|
S. A. Lagerstedt, D. J. O'Kane, and R. J. Singh Measurement of Plasma Free Metanephrine and Normetanephrine by Liquid Chromatography-Tandem Mass Spectrometry for Diagnosis of Pheochromocytoma Clin. Chem., March 1, 2004; 50(3): 603 - 611. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Ilias and K. Pacak Current Approaches and Recommended Algorithm for the Diagnostic Localization of Pheochromocytoma J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 479 - 491. [Full Text] [PDF]
|
|
|
|
|
|
I. Ilias, J. Yu, J. A. Carrasquillo, C. C. Chen, G. Eisenhofer, M. Whatley, B. McElroy, and K. Pacak Superiority of 6-[18F]-Fluorodopamine Positron Emission Tomography Versus [131I]-Metaiodobenzylguanidine Scintigraphy in the Localization of Metastatic Pheochromocytoma J. Clin. Endocrinol. Metab., September 1, 2003; 88(9): 4083 - 4087. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Bryant, J. Farmer, L. J. Kessler, R. R. Townsend, and K. L. Nathanson Pheochromocytoma: The Expanding Genetic Differential Diagnosis J Natl Cancer Inst, August 20, 2003; 95(16): 1196 - 1204. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C Bauters, M-C Vantyghem, E Leteurtre, M-F Odou, C Mouton, N Porchet, J-L Wemeau, C Proye, and P Pigny Hereditary phaeochromocytomas and paragangliomas: a study of five susceptibility genes J. Med. Genet., June 1, 2003; 40(6): e75 - 75. [Full Text] [PDF]
|
|
|
|
|
|
A. M. Sawka, R. Jaeschke, R. J. Singh, and W. F. Young Jr. A Comparison of Biochemical Tests for Pheochromocytoma: Measurement of Fractionated Plasma Metanephrines Compared with the Combination of 24-Hour Urinary Metanephrines and Catecholamines J. Clin. Endocrinol. Metab., February 1, 2003; 88(2): 553 - 558. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Weise, D. P. Merke, K. Pacak, M. M. Walther, and G. Eisenhofer Utility of Plasma Free Metanephrines for Detecting Childhood Pheochromocytoma J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 1955 - 1960. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. W. M. Lenders, K. Pacak, M. M. Walther, W. M. Linehan, M. Mannelli, P. Friberg, H. R. Keiser, D. S. Goldstein, and G. Eisenhofer Biochemical Diagnosis of Pheochromocytoma: Which Test Is Best? JAMA, March 20, 2002; 287(11): 1427 - 1434. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Eisenhofer Free or Total Metanephrines for Diagnosis of Pheochromocytoma: What Is the Difference? Clin. Chem., June 1, 2001; 47(6): 988 - 989. [Full Text] [PDF]
|
|
