Current Approaches and Recommended Algorithm for the Diagnostic Localization of Pheochromocytoma

Ioannis Ilias and Karel Pacak

Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1583

Address all correspondence and requests for reprints to: Karel Pacak, M.D., Ph.D., D.Sc., Unit on Clinical Neuroendocrinology, Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 100, Room 9D42, 10 Center Drive, Bethesda, Maryland 20892. E-mail: karel{at}mail.nih.gov.


    Introduction
 Top
 Introduction
 Anatomical imaging
 CT imaging
 MRI imaging
 U/S imaging
 Functional imaging
 MIBG imaging
 PET imaging
 Somatostatin receptor...
 Proposed imaging algorithm
 References
 
PHEOCHROMOCYTOMAS (PHEO) (1, 2, 3) are catecholamine-producing tumors that arise from chromaffin cells. PHEO are mostly situated within the adrenal medulla, although in about 9–23% of cases, tumors develop from extraadrenal chromaffin tissue (adjacent to sympathetic ganglia of the neck, mediastinum, abdomen, and pelvis) and are often referred to as paragangliomas (4, 5, 6).

PHEO situated in the adrenal gland are identified more commonly than those in extraadrenal tissues, because clinicians usually focus on the adrenal gland as a main source of catecholamine production. Although they usually choose a proper imaging technique to attempt the localization of PHEO in the adrenal gland, they are often confused as to which algorithm to follow and what technique to choose for the detection of extraadrenal PHEO. Furthermore, physicians often neglect the facts that up to approximately 25% of patients with apparent sporadic PHEO may, in fact, be carriers of germline mutations, indicating hereditary disease with a predisposition for extraadrenal, often multifocal, PHEO (7); that in children, multifocal and extraadrenal PHEO are found in up to 30–43% of cases (6, 8, 9, 10, 11, 12); that malignant PHEO account for up to 26–35% of cases (13, 14, 15, 16, 17, 18); that the prevalence of malignancy in sporadic adrenal PHEO is 9% (5); and that about 10% of patients with PHEO present with metastatic disease at the time of their initial work-up (19). After initial failed surgery, patients with metastatic PHEO are commonly reevaluated using metaiodobenzylguanidine (MIBG) scintigraphy, a modality that should actually be performed before surgery to confirm that a tumor was indeed a PHEO (5–9% of the population harbor an adrenal tumor, most commonly a benign adenoma) (20, 21, 22) or to rule out metastatic disease. These patients are then reoperated upon, suffering additional surgery-related complications and substantial financial expenses. Some clinicians consider the presence of sporadic unilateral small PHEO as indicative of benign disease. This was concluded in older studies of series of patients with PHEO (23, 24, 25). However, more recent works from large series of patients with benign and malignant disease in the United States and Europe do not support this view; rather, they support the opinion that there are no absolute clinical, imaging, or laboratory criteria to predict malignancy and clinical course of PHEO (5, 16, 19, 26, 27, 28, 29, 30, 31, 32). Nevertheless, PHEO tumors with a diameter larger than 5 cm have a higher potential to metastasize, and such patients should be followed more frequently (33). Consequently, it seems that ruling out metastatic PHEO before initial surgery would be useful, because the detection of other lesions may dramatically affect treatment and follow-up.

Localization of PHEO should be attempted using at least two imaging modalities. Anatomical imaging studies [computed tomography (CT) and magnetic resonance imaging (MRI)] should be combined with functional (nuclear medicine) imaging studies for optimal results to locate primary, recurrent, or metastatic PHEO.

Functional imaging studies (enabled by the presence of the noradrenergic transporter system on PHEO cells) include [123I]- or [131I]MIBG scintigraphy, 6-[18F]fluorodopamine ([18F]DA), [18F]dihydroxyphenylalanine ([18F]DOPA), [11C]hydroxyephedrine, and [11C]epinephrine positron emission tomography (PET) (34, 35, 36, 37, 38). Chromaffin cells in various neuroendocrine tissues [such as PHEO, but also medullary thyroid carcinoma (MTC)] express the plasma membrane norepinephrine transporter and the intracellular vesicular monoamine transporter. The norepinephrine transporter is responsible for the cellular uptake of both MIBG (39) and [18F]DA (36). We have recently shown that [18F]DA PET scanning could theoretically represent yet another imaging modality for the detection of MTCs (40) because MTC cells often express the norepinephrine transporter and concentrate MIBG (41).

In most cases, functional imaging modalities are either able to confirm that a tumor is a PHEO or can lead to further diagnostic work-up. For example, in a patient with positive plasma metanephrines and MIBG imaging studies showing uptake in extraadrenal locations, the possible presence of multiple endocrine neoplasia type 2 (MEN 2)-related tumors (including MTC) should be considered and assessed with measurement of serum calcitonin and/or RET mutations.

Functional imaging studies are also very helpful to rule out metastatic disease in most cases. However, as malignant PHEO may undergo tumor dedifferentiation with loss of specific neurotransmitter transporters (Refs. 42 and 43 , and Pacak, K., unpublished observation), leading to the inability to accumulate these isotopes and consequent lack of localization, [18F]fluorodeoxyglucose ([18F]FDG) PET scanning or somatostatin receptor scintigraphy (Octreoscan) may be required as the next step of the imaging algorithm. [18F]FDG is a nonspecific imaging agent whose accumulation is based on the higher metabolic rate of tumors compared with surrounding normal tissue. Another characteristic of dedifferentiated tumors is either the loss or the gain of specific receptors. More particularly, malignant PHEO often expresses somatostatin receptors (44, 45, 46, 47), thus enabling scintigraphy with the somatostatin analog octreotide.

In this review we provide readers with current views of the roles of various imaging modalities for biochemically proven PHEO based on elevated plasma metanephrines (36, 48, 49, 50) with emphasis on new functional PET imaging agents. Furthermore, we recommend an algorithm implementing anatomical and functional imaging modalities to assure proper localization of benign and malignant PHEO. The proposed algorithm serves not only to localize PHEO, but also to confirm that a tumor is indeed a PHEO and to differentiate adrenal tumors, including incidentalomas from PHEO. Whenever possible, in treating benign or malignant PHEO, surgical excision of any accessible mass should be considered (13, 51, 52, 53, 54), because it may alleviate symptoms from catecholamine excess, improve quality of life, and possibly in some patients with only osseous metastatic lesions help to increase their survival. However, in the presence of extensive organ metastatic lesions, the removal of primary lesions and incomplete removal of metastatic lesions in organs are not considered to have an effect on the patients’ survival (55), although further studies are needed. The proposed algorithm serves to guide and optimize surgery in patients with adrenal and extraadrenal PHEOs. Finally, although no cost-effectiveness analyses of PHEO localization have yet been performed, we believe that our approach deals with some "cost" issues, including less radiation exposure to patients.


    Anatomical imaging
 Top
 Introduction
 Anatomical imaging
 CT imaging
 MRI imaging
 U/S imaging
 Functional imaging
 MIBG imaging
 PET imaging
 Somatostatin receptor...
 Proposed imaging algorithm
 References
 
CT and MRI are common initial imaging modalities used for the localization of PHEO. These studies localize PHEO with high sensitivity, but less than optimal specificity. As these imaging modalities are currently less expensive and time consuming as well as more readily available than functional imaging studies, they should be used as first line imaging modalities. In addition, they should always be carried out over the abdomen first, because PHEO are mostly situated within the adrenal medulla. In some specific situations (see below), anatomical imaging for PHEO can be performed with ultrasound (U/S).

PHEO that secrete only epinephrine are uncommon, although they are frequently found in patients with MEN 2 (56). Patients with PHEO that secrete only epinephrine have high plasma or urinary epinephrine or metanephrine levels, and almost always have an adrenal tumor. In these patients, CT or MRI of the abdomen are a first choice examination for the diagnostic localization of PHEO. On the other hand, norepinephine and normetanephrine can be secreted by PHEO localized both within and outside the adrenal gland (48). If no adrenal masses are seen, attention should be focused initially to the paraspinous area (57). The majority of paragangliomas occur in the paraaortic region or around the renal hilum and may be visible on CT/MRI (57).


    CT imaging
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 Introduction
 Anatomical imaging
 CT imaging
 MRI imaging
 U/S imaging
 Functional imaging
 MIBG imaging
 PET imaging
 Somatostatin receptor...
 Proposed imaging algorithm
 References
 
Adrenal PHEO of 0.5–1.0 cm or larger or metastatic PHEO at least 1.0–2.0 cm in size can be detected by CT (36, 58), preferably with 2- to 5-mm-thick scanning sections (59). As most adrenal PHEO tumors have a diameter of at least 3 cm, they can be readily visualized with CT (Fig. 1AGo). Adrenal adenomas can be differentiated from metastases with CT densitometry (60, 61, 62). More particularly, a homogenous mass with a density measurement of less than 10 Hounsfield units (HU) on an unenhanced CT is most probably an adenoma (62), whereas if the mass is inhomogeneous and/or has a density measurement of 10 HU or more, the diagnosis is uncertain. Although nonfunctioning adenoma is the most common possibility, a metastasis or functioning tumor should also be considered. For cases with inconclusive clinical and biochemical results, further imaging assessment should be sought using washout after administration of contrast medium (61, 63). Small 1- to 2-cm PHEO tumors are usually homogeneous in appearance, with soft tissue density (~40–50 HU) and show uniform enhancement with contrast (64). Larger PHEO tumors may undergo hemorrhage and can be inhomogeneous, and areas of low density can be seen after tumor necrosis (57, 64, 65, 66).



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FIG. 1. A, Abdominal CT of a 44-yr-old man with MEN 2A. Bilateral adrenal PHEOs (5–6 cm in maximum diameter) are evident (arrows); the lesion in the left adrenal appears to be bilobed. B, Abdominal T2-weighted MRI scans of the same patient. The bilateral adrenal PHEOs show a characteristically high signal (arrows). Both tumors were hemorrhagic, and the left PHEO was cystic, which explains their relative inhomogeneity of appearance.

 
Extraadrenal PHEO are located close to the inferior vena cava and the abdominal aorta and alongside the sympathetic ganglia and Zuckerkandl’s organ (7–10%), between the inferior mesenteric artery and the aortic bifurcation, in the mediastinum (1%), or near the urinary bladder (1%) (33, 59). Thus, CT of the abdomen and pelvis should be performed first, followed by chest and neck imaging if this CT is negative (33, 66, 67, 68, 69, 70, 71, 72, 73). Spiral CT is preferred for small thoracic tumors.

The advantages of CT in the localization of PHEO are the moderate cost and its high sensitivity, which varies between 85–94% if a PHEO is located in the adrenal gland (19, 58, 74, 75). Sensitivity for detecting extraadrenal, metastatic, or recurrent PHEO is about 90% before surgery (58, 76, 77). The sensitivity of CT may decrease to about 77% due to postoperative changes (35, 77). Additionally, the specificity of CT in excluding PHEO has been shown to be limited in some studies, from 29–50% (75, 78, 79). Nevertheless for lesions limited to the adrenal glands, unenhanced CT followed by contrast-enhanced and delayed contrast-enhanced CT imaging yields a sensitivity of 98% and a specificity of 92% (63, 80). CT shows the structures surrounding a PHEO and permits exact localization of the tumor, although intraabdominal foreign bodies, such as surgical clips, may distort imaging findings (81, 82). In some patients with PHEO, CT may be negative or have equivocal findings, whereas MRI exams are positive (83, 84), but these cases are rare, especially in patients with no history of previous operation. Traditionally, {alpha}- and possibly also ß-adrenergic receptor antagonist administration is advised for patients with biochemically proven PHEO to safely give ionic monomeric iv contrast for enhanced CT examination (64, 85, 86). However, no rise in plasma catecholamines was observed in 10 patients with PHEO who were given ioexol, a nonionic contrast medium, iv (85), so even contrast-enhanced CT does not pose a significant risk of a hypertensive crisis.

If a high quality, unenhanced and delayed enhanced, CTs are performed and the PHEO tumor is localized, there is no need to proceed to MRI, but functional imaging is required to confirm that a tumor is indeed PHEO and to rule out metastatic disease. If the CT is negative, in a patient with biochemically proven PHEO, MRI should be performed. MRI should be substituted for CT in children, pregnant women, and situations where radiation exposure must be minimized (87). Other situations where MRI is needed in addition to/instead of CT are described below.


    MRI imaging
 Top
 Introduction
 Anatomical imaging
 CT imaging
 MRI imaging
 U/S imaging
 Functional imaging
 MIBG imaging
 PET imaging
 Somatostatin receptor...
 Proposed imaging algorithm
 References
 
Another imaging modality that is widely used in the diagnostic work-up of adrenal PHEO or detection of metastatic disease is MRI, with or without gadolinium enhancement (36, 58, 88). On MRI T1 sequences, PHEO have a signal like those of the liver, kidney, and muscle and can be differentiated with ease from adipose tissue. Chemical shift MRI characterizes adrenal masses based on the presence of fat in benign adenomas and the absence of fat in PHEO, metastases, hemorrhagic pseudocysts, or malignant tumors (89, 90, 91, 92, 93, 94, 95). The hypervascularity of PHEO makes them appear characteristically bright, with a high signal on T2 sequence (Fig. 1BGo) and no signal loss on opposed phase images (Fig. 1BGo) (96). More particularly, almost all PHEO have a more intense signal than that of the liver or muscle and often more intense than fat on T2-weighted images (57, 65, 97). However, such intense signals can be elicited by hemorrhages or hematomas, adenomas, and carcinomas, so an overlap with PHEO must be considered (98, 99, 100, 101), and specific additional imaging is needed to confirm that the tumor is PHEO. Atypical PHEO may show medium signal quality on T2-weighted images and an inhomogeneous appearance, especially if they are cystic (102).

Among the advantages of MRI imaging of PHEO are its high sensitivity in detecting adrenal disease (93–100%) (19, 74, 103) and the lack of exposure to ionizing radiation. MRI is a good imaging modality for the detection of intracardiac, juxtacardiac, and juxtavascular PHEO, because it reduces cardiac and respiratory motion-induced artifacts (102), whereas the use of T2 sequences enables better differentiation from surrounding tissues (104). MRI can be carried out with or without using iv contrast agents (which are nevertheless very safe and do not cause the release of catecholamines) (105, 106, 107), and thus no preparation with adrenergic blockade is necessary. MRI offers the possibility of multiplanar imaging and superior assessment of the relationship between a tumor and its surrounding vessels (the great vessels in particular) compared with CT, rendering this modality of utmost importance in the evaluation of patients with PHEO in these areas, especially to rule out vessel invasion (75). However, its overall sensitivity for detection of extraadrenal, metastatic, or recurrent PHEO is lower compared with that of adrenal disease (90%) (58, 75, 76, 108). Although some researchers have reported high specificity of MRI in excluding PHEO (100%) (79), in most reports the specificity of this modality has been shown to be limited to about 50% (74, 75). Additionally, MRI is a more expensive imaging modality than CT.

MRI should be used as the initial imaging procedure for imaging PHEO in children or during pregnancy (36, 108, 109), because it does not involve any radiation exposure, or in the case of known allergy to CT contrast agents.


    U/S imaging
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 Introduction
 Anatomical imaging
 CT imaging
 MRI imaging
 U/S imaging
 Functional imaging
 MIBG imaging
 PET imaging
 Somatostatin receptor...
 Proposed imaging algorithm
 References
 
On U/S imaging, PHEO are usually seen as well defined, round or ovoid masses that demonstrate low echogenicity and homogenous consistency (64, 110). Large PHEO tumors frequently undergo hemorrhage or necrosis, and in this case homogeneity is lost (64). The sensitivity of U/S in evaluating PHEO has been assessed in relatively small numbers of patients and has been reported to be 83–89% (87, 111). To the best of our knowledge, extensive studies on the specificity of modern U/S techniques in the diagnosis of PHEO have not been performed, but it is believed to be low, as in older studies where the overall specificity for adrenal tumors was about 60% (112). As U/S is a modality with no radiation exposure, it can be a first-line choice in the diagnostic work-up of PHEO in selected patients, such as pregnant women (113, 114), infants, and children (34), but it is not superior to MRI. The low cost and ease of using U/S make this imaging modality a sound choice in the initial evaluation of patients suspected of having PHEO in the neck (115). However, 10% of PHEO are cystic, and although they are readily seen with U/S, those located in the adrenal gland must be differentiated from upper pole renal cysts and hepatic cysts (34). Familial/hereditary causes of PHEO (such as MEN 2 syndrome, von Hippel-Lindau disease, or neurofibromatosis type 2) and possibly, in part, referral bias may account for the high prevalence of multifocal (adrenal and extraadrenal) or only extraadrenal PHEO reported in studies of children (diagnosed in up to 30–43% of cases) (6, 8, 9, 10, 11, 12). As U/S provides limited views of the abdomen (108), it is inherently insensitive for imaging extraadrenal PHEO and cannot rule out multifocal disease. Similar to CT/MRI, the presence of surgical clips, distorted anatomy, or inadequate preparation of the patient may also render the interpretation of U/S images difficult.

In summary, this modality is not suitable for evaluating adult patients, and we do not recommend it unless under specific conditions (e.g. pregnancy) and in cases where CT and MRI are not available.


    Functional imaging
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 Introduction
 Anatomical imaging
 CT imaging
 MRI imaging
 U/S imaging
 Functional imaging
 MIBG imaging
 PET imaging
 Somatostatin receptor...
 Proposed imaging algorithm
 References
 
Adrenal masses are present in about 5–9% of the general population (21, 22, 116, 117). Although most adrenal masses are benign, nonfunctional incidentalomas, about 6.5% of incidentally discovered adrenal masses are indeed PHEO (1, 2, 3). Thus, most adrenal abnormalities are not PHEO, highlighting the need for specific diagnostic imaging after anatomical studies are performed in patients with suspicion of PHEO. Additionally, as previously stated, there is no consensus on the existence of absolute clinical, imaging, or laboratory criteria to predict malignancy and multiplicity of PHEO (26, 27, 28). Thus, in patients diagnosed with PHEO, the need to exclude metastatic disease or multiple tumors is important. This need might be fulfilled with functional imaging modalities using various radiopharmaceuticals that provide physicians with whole body, PHEO-specific, scans. Nuclear medicine imaging is also important in localizing PHEO in patients in whom anatomic imaging is negative and in the detection of metastatic lesions. However, all functional imaging methods are hampered by the excretion of radioisotopes in urine (118, 119, 120, 121), thus lowering their ability to localize PHEO close to the kidneys, the head of the pancreas, or the urinary bladder.

PHEO cells usually abundantly express specific catecholamine plasma membrane and vesicular transporter systems, enabling imaging with [131I]- and [123I]MIBG, as well as with several PET ligands (118, 120). In Table 1Go, we present a list of available radiopharmaceuticals for localization of PHEO. Some are already in clinical use, whereas newer ones are currently undergoing evaluation (122, 123, 124).


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TABLE 1. Radiopharmaceuticals Used for Nuclear Medicine Imaging Studies of PHEO in Research and Clinical Practice (Modified in Part from Ref.34 )

 

    MIBG imaging
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 Introduction
 Anatomical imaging
 CT imaging
 MRI imaging
 U/S imaging
 Functional imaging
 MIBG imaging
 PET imaging
 Somatostatin receptor...
 Proposed imaging algorithm
 References
 
MIBG is an aralkylguanidine that resembles norepinephrine. Radioactive labeling is performed with the iodine isotopes131I and 123I at the meta-position of the benzoic ring. Like norepinephrine, MIBG is taken into sympathomedullary tissues mainly by a noradrenergic transporter system and into intracytoplasmic vesicles through a vesicular transporter system. MIBG is thus accumulated within adrenergic tissues. However, MIBG does not show any appreciable binding to adrenergic receptors and is minimally metabolized. The plasma membrane and vesicular uptake is Na+ dependent and can be influenced by medications such as certain nasal decongestants, antihypertensives, antidepressants, and antipsychotics, as well as by cocaine (125); all have to be withheld for 1–3 d, depending on the medications, with the exception of depot forms of antipsychotics, for which the withdrawal period suggested is 1 month (125), before undergoing this nuclear medicine examination. Labetalol, in particular, has been shown to significantly reduce [131I]- and [123I]MIBG uptake (126, 127, 128).

[131I] has a long half-life (8.2 d) and emits high energy {gamma}-radiation (364 keV). For imaging, [131I]MIBG is administered iv at doses ranging from 0.5–1.0 mCi (18.5–37 MBq) or 0.5 mCi (18.5 MBq)/1.7 m2, resulting in an absorbed dose at the adrenals of 1 Gy/mCi (129).

123I has a shorter half-life (13 h) and emits lower energy {gamma}-radiation (159 keV) than 131I. [123I]MIBG is administered iv at doses ranging from 3 mCi in children to 10 mCi in adults (130). The absorbed radiation dose from 10 mCi (370 MBq) [123I]MIBG approaches that of 0.5 mCi (18.5 MBq) [131I]MIBG (131). Currently, however, its availability in the United States is rather limited.

The amount of free 131I in [131I]MIBG is less than 5% (132, 133), and after administration, MIBG releases a further small percentage (~3%) of free 131I (132, 133). To block thyroid accumulation of the free 131I, which may obscure neck paragangliomas and prevent thyroid damage, patients should take a saturated solution of potassium iodide (100 mg twice a day), or in the case of allergy to a saturated solution of potassium iodide, potassium perchlorate should be given (200–300 mg or 15 drops of perchlorate solution twice a day), starting 1 d before the patient receives MIBG, for 4 or 7 d after administration of [123I]- or [131I]MIBG, respectively. Despite the use of blockade, a slight risk of decreased thyroid function persists, as seen in experimental conditions with rats (134) and in children who have received larger doses of [131I]MIBG for therapy of neuroendocrine tumors (135, 136).

Scintigraphy is performed after 24 h and, if necessary, at 48 h for [123I]MIBG. For [131I]MIBG, imaging is performed at 24 and 48 h and, if necessary, at 72 h.

Normally, the myocardium, spleen, liver, urinary bladder, lungs, and salivary glands, being rich in sympathetic innervation, show MIBG uptake after 24 h (137, 138, 139, 140, 141, 142). On some occasions, the large intestine (143) and the cerebellum (144, 145) may also show MIBG accumulation. Moreover, the normal adrenal medulla may show [123I]MIBG uptake (in as many as 32–75% of patients after 24 h) (130, 140). The pattern of [123I]MIBG uptake may be asymmetrical between the left and right adrenals, and caution should be applied in interpreting the images obtained, particularly to avoid unnecessary or misguided surgery. More rarely, [131I]MIBG uptake is seen in normal adrenal medulla (16% of scans after 48 h) (141). Some of the MIBG is taken up by platelets, and thrombocytopenia may occur (146, 147). Most of the injected MIBG is excreted via the kidneys, with minimal excretion in sweat, saliva, and feces (118, 148).

[131I]- and [123I]MIBG scintigraphy has been used extensively in the work-up of patients with PHEO (122, 149, 150, 151, 152). PHEOs appear as areas of abnormal increased MIBG uptake (Fig. 2AGo). With [123I]MIBG, single photon emission CT (SPECT) is usually carried out (153). [123I]MIBG is particularly useful in detecting recurrent or metastatic PHEO, tumors with fibrosis, or tumors in unusual locations or in areas with distorted anatomy (150, 154, 155).



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FIG. 2. A, [123I]MIBG scan of a 63-yr-old patient with a right adrenal PHEO. One focus of uptake is seen (arrow). B, When the same patient was studied with [18F]DA PET, two foci of uptake were seen (arrows).

 
[131I]MIBG scintigraphy has a sensitivity ranging from 77–90% and a high specificity (95–100%) for PHEO (151, 152, 156, 157). Likewise, [123I]MIBG scintigraphy has a sensitivity ranging from 83–100% and a high specificity (95–100%) for PHEO (156, 158). In the clinical setting, for most, but not all, patients, a negative result on [131I]- or [123I]MIBG scintigraphy excludes a diagnosis of PHEO, whereas abnormal uptake on [131I]- or [123I]MIBG scintigraphy usually confirms the presence of PHEO. Rarely, false positive [131I]MIBG examinations have been reported in cases of adrenal carcinoma (159) and in infectious lesions such as actinomycosis (160). False negative MIBG examinations may be expected in cases of nonadherence, with instructions to stop medications that interfere with MIBG uptake (125), and with PHEO tumors that have undergone necrosis or dedifferentiated PHEO tumors. Adrenal adenomas have caused false positive [123I]MIBG uptake (161), and anatomical variations of the renal pelvis may also lead to false positive imaging results (162). The higher sensitivities and the option of using SPECT (156, 163, 164, 165) lead us to recommend [123I]MIBG over [131I]MIBG scintigraphy wherever possible. Fusion imaging techniques of [123I]MIBG with CT/MRI, although not yet in widespread use, hold great diagnostic potential in the evaluation of patients with PHEO (151).


    PET imaging
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 Introduction
 Anatomical imaging
 CT imaging
 MRI imaging
 U/S imaging
 Functional imaging
 MIBG imaging
 PET imaging
 Somatostatin receptor...
 Proposed imaging algorithm
 References
 
PET imaging is performed within minutes or hours after the injection of short-lived positron-emitting agents. Low radiation exposure and superior spatial resolution are among the advantages of PET, whereas the cost and limited availability of the radiopharmaceuticals and PET equipment (including the radionuclide-producing cyclotron) still prohibit more widespread use. In the evaluation of patients with PHEO, PET with [18F]FDG, [11C]hydroxyephedrine, or [11C]epinephrine have been used most often (37, 166, 167, 168, 169). [18F]DOPA is also used, and at the NIH, [18F]DA has been used with success (35, 36).

Increased glucose metabolism characterizes various malignant tumors; thus, the uptake of glucose labeled with [18F]fluoride (half-life, 110 min) can, in theory, be useful in the imaging of these tumors (Fig. 3Go). In one study of 17 patients, [18F]FDG PET was used with some success for imaging metastatic PHEO and revealed more metastases than [123I]MIBG or [131I]MIBG scans (168). Malignant PHEO may accumulate [18F]FDG more avidly compared with benign PHEO; nevertheless, semiquantitative analysis of standardized uptake values of images obtained with FDG-PET could not distinguish malignant from benign disease (168). Imaging with FDG-PET may be good for localizing dedifferentiated and/or rapidly growing PHEO tumors. Unfortunately, all rapidly metabolizing cells take up glucose, so imaging with [18F]FDG PET remains nonspecific for PHEO and should never be used as an initial study.



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FIG. 3. [18F]FDG PET-reprojected image of a 22-yr-old female patient with a right PHEO. Radionuclide uptake is evident over the right adrenal (arrow). Studies with [123I]MIBG and Octreoscan were negative.

 
In terms of diagnostic localization of PHEO, [11C]hydroxyephedrine and [11C]epinephrine PET have also detected PHEO tumors (37, 166, 167, 168). In the most recent study with [11C]hydroxyephedrine PET, radionuclide uptake was seen in eight of 18 patients (37). [11C]Hydroxyephedrine-derived radioactivity appears to decline relatively rapidly from chromaffin cells, possibly because of less efficient vesicular sequestration of this sympathomimetic amine compared with catecholamines. Moreover, epinephrine is a poor substrate for the norepinephrine transporter compared with DA. Among the other shortcomings of [11C]hydroxyephedrine and [11C]epinephrine is the short half-life of [11C]radiopharmaceuticals (20 min), which renders the implementation of whole body scans difficult. Short half-lives and high costs are also important deterrents to their more widespread availability, as an on-site cyclotron is then needed for production. The same agents that inhibit uptake of MIBG may also inhibit uptake of [11C]metahydroxyephedrine and [11C]epinephrine (168).

[18F]DOPA is a precursor of DA and has also been used in patients with PHEO. Normal adrenals do not show [18F]DOPA uptake. [18F]DOPA was used in a study of 14 patients with benign adrenal PHEO and a small number of patients (n = 3) with extraadrenal, but not metastatic, PHEO (38). In the former group, all tumors were localized with [18F]DOPA PET, whereas in the latter group [18F]DOPA PET imaging was concordant with MRI results in one of three patients and imaged a tumor that was not seen with [131I]MIBG scintigraphy (38). In a recent study of 10 patients with glomus jugulare tumors (which are similar to PHEO, as they arise from the paraganglionic tissue of the head and neck), 11 of the 15 presumed tumors diagnosed by [18F]DOPA PET were confirmed by MRI (170).

DA is a more specific substrate for the norepinephrine transporter compared with most other amines, including norepinephrine or DOPA (171). Consequently, an analog of DA should be a better imaging agent than norepinephrine or DOPA. In view of this, a new sympathoneural imaging agent, [18F]DA, was developed at the NIH. [18F]DA is a positron-emitting analog of DA and a good substrate for both the plasma membrane and intracellular vesicular transporters in catecholamine-synthesizing cells. Administration of [18F]DA results in a tissue-blood concentration ratio of more than 1000 and enables good visualization of these cells (171). Our experience has shown that [18F]DA is an excellent agent to localize adrenal and extraadrenal PHEO, including metastatic lesions (172, 173) (Figs. 2BGo and 4Go). We recently published a study of a series of 28 patients with known PHEO in whom [18F]DA PET scans were positive and localized PHEO tumors in all (172). We have also seen patients with negative [131I]MIBG scans, but positive [18F]DA scans, especially in the setting of metastatic PHEO (174) (Pacak, K., unpublished observations). Furthermore, in 15 patients with biochemically proven PHEO (elevated plasma free metanephrines), [18F]DA PET studies were positive in all, corroborating metastatic disease and providing more accurate information about the number and location of metastatic lesions compared with [131I]MIBG (173).



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FIG. 4. [18F]DA PET-reprojected image of a 25-yr-old male patient with a pelvic primary PHEO tumor (P) and multiple metastatic lesions in the right humerus, pelvis, abdomen, mediastinum, and thorax (arrows). The renal calyces and the ureters are prominent.

 
We believe that [18F]DA PET in particular offers several advantages as a functional imaging agent in PHEO. First, [18F]DA PET results in a lower total cumulative radiation dose than [131I]MIBG (131, 175, 176); the latter also necessitates thyroid blocking with administration of iodine. Moreover, PET scanning is carried out immediately after the administration of [18F]DA, as opposed to the 24- to 48-h delay necessary for [131I]MIBG scanning, and yields tomographic images as opposed to the planar images. [18F]DA is also more specific for PHEO than other amines such as DOPA, because the latter are taken up as amines by all body cells and are converted to DA. A major disadvantage of [18F]DA PET scanning, however, is that this agent is currently available in only a few clinical centers. Further studies are needed to compare [123I]MIBG with [18F]DA.


    Somatostatin receptor scintigraphy
 Top
 Introduction
 Anatomical imaging
 CT imaging
 MRI imaging
 U/S imaging
 Functional imaging
 MIBG imaging
 PET imaging
 Somatostatin receptor...
 Proposed imaging algorithm
 References
 
Somatostatin receptors have seven transmembrane domains and are G protein coupled (177). Five types of somatostatin receptors are recognized. Types 1, 2, and 5 are abundantly expressed in different neuroendocrine tumors, whereas type 4 shows variable expression, and type 3 shows low expression in these tumors (177, 178). Up to 73% of PHEO cells express somatostatin receptors (predominantly types 2 and 4) (47), like other neuroendocrine tumors, as shown by studies using different techniques, such as radioligand binding, immunohistochemistry, in situ hybridization, Northern blotting, ribonuclease protection, and quantitative RT-PCR (179, 180, 181). Octreotide is an eight-amino acid-long peptidic analog of somatostatin that is metabolically stable and has highest affinity for type 2 somatostatin receptors, high affinity for type 5 receptors, moderate affinity for type 3 receptors, and no affinity for types 1 and 4 receptors of somatostatin (182). [111In]diaminetriaminepentacetate (DTPA), with a half-life of 2.8 d and {gamma}-ray emissions of 173 and 247 keV, is usually used for labeling octreotide. Octreotide is internalized through a receptor-mediated process, and conjugation with DTPA (which is a polar molecule) prevents its passage across the lysosomal and other cell membranes (177).

Octreotide is given iv in doses of 3–6 mCi (111–222 MBq), and scintigraphic views are obtained at 4, 24, and 48 h, as needed. SPECT imaging should be performed. Octreotide is predominantly (85%) cleared by the kidneys within 24 h (119, 121). Sites of physiological uptake include mammary glands, liver, spleen, kidneys, bowel gall bladder, pituitary, thyroid, and salivary glands (119, 120, 121, 183). Infections, inflammation, and recent surgery cause false positive results (184, 185). Inflamed joints in patients with arthritis also show increased octreotide uptake (34).

Somatostatin receptor scintigraphy (with either [123I]Tyr3-octreotide or [111In]DTPA-octreotide) has been used in patients with PHEO (46, 186, 187, 188, 189, 190, 191). However, the interpretation of the Octreoscan is hampered by the normal presence of somatostatin receptors in a wide range of tissues as well as in inflammatory sites. Another drawback to imaging of intraadrenal PHEO with Octreoscan is the significant degree of octreotide uptake seen in the kidneys (192, 193), which reduces the scintigraphic sensitivity of [111In]DTPA-octreotide for small tumors in the perirenal region (192, 193), and although the infusion of amino acid solutions such as lysine and arginine can lower renal uptake, this technique is not yet widely implemented (194). Metastatic PHEO may also show tumor dedifferentiation, resulting in the loss of somatostatin receptors (46, 47), and consequently, negative [111In]DTPA-octreotide studies can also be expected in these patients.

Only a few reports have compared [123I]MIBG/[131I]MIBG with Octreoscan by studying them in the same patients with PHEO (156, 165, 188, 190, 191). Published reports have not found somatostatin receptor scintigraphy to be helpful in the localization of primary PHEO tumors (156), with Octreoscan studies being negative in most patients (66–75%) with benign PHEO (despite positive [123I]MIBG or [131I]MIBG studies) (77, 156). Malignant/metastatic PHEO are better detected with Octreoscan compared with [123I]MIBG (finding 87% vs. 57% of lesions) (156), because MIBG as well as [18F]DA are sometimes negative in patients with malignant PHEO, possibly because of decreased expression of the cell membrane norepinephrine transporter by less well differentiated cells (42, 43) (Pacak, K., unpublished observations). In such cases, Octreoscan should be performed to localize PHEO, because this modality has detected lesions in patients with MIBG-negative neuroendocrine tumors (156, 188, 191, 195) (Fig. 5Go). This is more important, as more metastases of undifferentiated neuroendocrine tumors were positive on Octreoscan compared with metastases of histologically well differentiated neuroendocrine tumors (195).



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FIG. 5. Widespread metastatic disease with lesions in the chest, abdomen, right acetabulum, and right thigh (arrows) seen on an Octreoscan of a 47-yr-old patient with recurrent PHEO. Uptake of octreotide in the right kidney is prominent (asterisk). In this patient, [123I]MIBG studies did not show definite foci of uptake.

 
We currently do not recommend performing PET, MIBG scintigraphy, or Octreoscan as the first imaging modalities in the diagnostic localization of PHEO, because of limited availability compared with CT/MRI and the long waiting time (up to 72 h) for obtaining imaging views, although these modalities are of utility in further diagnostic work-up of PHEO (156, 187).


    Proposed imaging algorithm
 Top
 Introduction
 Anatomical imaging
 CT imaging
 MRI imaging
 U/S imaging
 Functional imaging
 MIBG imaging
 PET imaging
 Somatostatin receptor...
 Proposed imaging algorithm
 References
 
A generally accepted and cost-effective approach for the diagnostic localization of PHEO has yet to be established. Biochemical confirmation of the disease is crucial (36, 48, 49) and is best achieved by measuring plasma metanephrine and normetanephrine, ensuring, however, adequate withdrawal from medications that interfere with these measurements and lead to false positive results, such as phenoxybenzamine, tricyclic antidepressants, and ß-adrenoreceptor blockers (196). Additional biochemical confirmation can be obtained using the clonidine test coupled with measurement of plasma metanephrine and normetanephrine (196, 197). Evaluation aiming to localize PHEOs in the absence of biochemical corroboration is justified only when there is suspicion of familial disease, particularly at a stage before these tumors secrete significant amounts of catecholamines (197).

In Fig. 6Go, we propose the use of anatomical imaging methods (either CT or MRI) for initial imaging of the adrenals in patients with biochemically proven PHEO. In some cases, such as in children or during pregnancy, MRI is preferred, but ultrasound may also be considered.



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FIG. 6. Algorithm for diagnostic localization of PHEO. +(+T2), Positive T1- and T2-weighted MRI examinations; +(-T2), positive T1- and negative T2-weighted MRI examinations; +, examination positive for tumor; -, examination negative for tumor; *, [123I]MIBG scintigraphy preferred over [131I]MIBG scintigraphy, where available; **, unusual types of PHEOs may not express the norepinephrine transporter system or may have a low number of catecholamine storage granules.

 
As far as CT is concerned, lesions on unenhanced CT with attenuation values lower than 10 HU exclude the presence of PHEO, whereas those with values higher than 10 HU may be followed by contrast-enhanced and delayed enhanced CT examinations (61, 63). If MRI is chosen as the initial anatomical imaging modality, T1 (with chemical shift) and T2 sequences should be performed. Negative CT or MRI imaging of the adrenals, abdomen, and pelvis should be followed by additional CT scans, except where this modality in contraindicated, such as in children and during pregnancy, where MRI is preferred. If all CT scans are negative, little is to be gained by performing MRI, except in patients with previous surgery that may result in distorted anatomy.

The presence of PHEO should always be ruled out or confirmed with functional imaging (even if CT and MRI are negative, but PHEO is biochemically proven). The functional imaging test of choice is [123I]MIBG, or, if this is not available, then [131I]MIBG should be performed. If the MIBG scan is negative, PET studies should be performed with specific ligands, preferably [18F]DA or [18F]DOPA. If these are also negative, the patient probably has an unusual type of PHEO (in which tumor cells do not express the norepinephrine transporter system or may have a low number of catecholamine storage granules) or malignant PHEO, and scintigraphy with nonspecific ligands, such as somatostatin receptor scintigraphy with Octreoscan or FDG PET, should be carried out. Venous sampling coupled with measurement of catecholamines or, preferably, metanephrines (35, 36, 50) to localize the tumor through the discovery of a secretory gradient is an ultimate modality to be used with caution in selected cases where all imaging methods have failed. This is technically demanding and is best conducted at specialized centers (6, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214). If access to such centers is not feasible, then a repeat noninvasive localization work-up after 2–6 months is a more attractive and preferable choice.


    Acknowledgments
 
We thank Clara C. Chen, M.D., for her critical review of the manuscript and her insightful comments; Millie Whatley, C.N.M.T., for assistance with preparing this manuscript; and Nikos A. Kourkoutsakis, M.D., Ph.D., and Eleni Liapi, M.D., for advice on technical issues.


    Footnotes
 
Abbreviations: CT, Computed tomography; DA, dopamine; DOPA, dihydroxyphenylalanine; DTPA, diaminetriaminepentacetate; FDG, fluorodeoxyglucose; HU, Hounsfield units; MEN 2, multiple endocrine neoplasia type 2; MIBG, metaiodobenzylguanidine; MRI, magnetic resonance imaging; MTC, medullary thyroid carcinoma; Octreoscan, somatostatin receptor scintigraphy with [123I]Tyr3-octreotide or [111In]diaminetriaminepentacetate-octreotide; PET, positron emission tomography; PHEO, pheochromocytoma; SPECT, single photon emission computed tomography; U/S, ultrasound.

Received June 25, 2003.

Accepted October 31, 2003.


    References
 Top
 Introduction
 Anatomical imaging
 CT imaging
 MRI imaging
 U/S imaging
 Functional imaging
 MIBG imaging
 PET imaging
 Somatostatin receptor...
 Proposed imaging algorithm
 References
 

  1. Pacak K, Chrousos GP, Koch CA, Lenders JW, Eisenhofer G 2001 Pheochromocytoma: progress in diagnosis, therapy, and genetics. In: Margioris AN, Chrousos GP, eds. Adrenal disorders. Totowa: Humana Press; 479–523
  2. Manger WM, Gifford Jr RW 1995 Pheochromocytoma. In: Swales JD, ed. Manual of hypertension. Boston: Blackwell; 102–110
  3. Manger WM, Gifford Jr RW 1996 Clinical and experimental pheochromocytoma, 2nd Ed. Cambridge: Blackwell
  4. Walther MM, Keiser HR, Linehan WM 1999 Pheochromocytoma: evaluation, diagnosis, and treatment. World J Urol 17:35–39[CrossRef][Medline]
  5. Bravo EL, Tagle R 2003 Pheochromocytoma: state-of-the-art and future prospects. Endocr Rev 24:539–553[Abstract/Free Full Text]
  6. Kuchel O 1983 Pheochromocytoma. In: Genest J, Kuchel O, Hamet P, Cantin M, eds. Hypertension: physiopathology and treatment, 2nd Ed. New York: McGraw-Hill; 947–963
  7. Neumann HPH, Bausch B, McWhinney SR, Bender BU, Gimm O, Franke G, Schipper J, Klisch J, Altehoefer C, Zerres K, Januszewicz A, Eng C 2002 Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 346:1459–1466[Abstract/Free Full Text]
  8. Khafagi FA, Shapiro B, Fischer M, Sisson JC, Hutchinson R, Beierwaltes WH 1991 Phaeochromocytoma and functioning paraganglioma in childhood and adolescence: role of iodine 131 metaiodobenzylguanidine. Eur J Nucl Med 18:191–198[Medline]
  9. Caty MG, Coran AG, Geagen M, Thompson NW 1990 Current diagnosis and treatment of pheochromocytoma in children. Arch Surg 125:978–981[Abstract]
  10. Newman KD, Ponsky T 2002 The diagnosis and management of endocrine tumors causing hypertension in children. Ann NY Acad Sci 970:155–158[Abstract/Free Full Text]
  11. Hoeffel JC, Galloy MA, Hoeffel C, Mainard L 2001 Les pheochromocytomes chez l’enfant. Ann Med Intern 152:363–370
  12. Levine LS, DiGeorge AM 2000 Pheochromocytoma. In: Behrman RE, Kliegman RM, Jenson HB, eds. Nelson textbook of pediatrics, 16th Ed. Philadelphia: Saunders; 1741–1743
  13. Mundschenk J, Lehnert H 1998 Malignant pheochromocytoma. Exp Clin Endocrinol Diabetes 106:373–376[Medline]
  14. Averbuch SD, Steakley CS, Young RC, Gelman EP, Goldstein DS, Stull B, Keiser HR 1988 Malignant pheochromocytoma: effective treatment with a combination of cyclophosphamide, vincristine and dacarbazine. Ann Intern Med 109:267–273[Medline]
  15. Mornex R, Badet C, Peyrin L 1992 Malignant pheochromocytoma: a series of 14 cases observed between 1966 and 1990. J Endocrinol Invest 15:643–649[Medline]
  16. Proye C, Vix M, Goropoulos A, Kerlo P, Lecomte-Houcke M 1992 High incidence of malignant pheochromocytoma in a surgical unit. 26 cases out of 100 patients operated from 1971 to 1991. J Endocrinol Invest 15:651–663[Medline]
  17. Tischler A 1998 The adrenal medulla and extra-adrenal paraganglia. In: Kovacs K, Asa S, eds. Functional endocrine pathology. Oxford: Blackwell; 550–595
  18. Whalen RK, Althausen AF, Daniels GH 1992 Extra-adrenal pheochromocytoma. J Urol 147:1–10[Medline]
  19. Goldstein RE, O’Neil Jr JA, Holcomb GW, Morgan WM, Neblett WW, Oates JA, Brown N, Nadeau J, Smith B, Page DL, Abumrad NN, Scott Jr HW 1999 Clinical experience over 48 years with pheochromocytoma. Ann Surg 229:755–766[CrossRef][Medline]
  20. Kloos RT, Gross MD, Francis IR, Korobkin M, Shapiro B 1995 Incidentally discovered adrenal masses. Endocr Rev 16:460–484[Abstract]
  21. Grumbach MM, Biller BM, Braunstein GD, Campbell KK, Carney JA, Godley PA, Harris EL, Lee JK, Oertel YC, Posner MC, Schlechte JA, Wieand HS 2003 Management of the clinically inapparent adrenal mass ("incidentaloma"). Ann Intern Med 138:424–429[Abstract/Free Full Text]
  22. Hedeland H, Ostberg G, Hokfelt B 1968 On the prevalence of adrenocortical adenomas in an autopsy material in relation to hypertension and diabetes. Acta Med Scand 184:211–214[Medline]
  23. Medeiros LJ, Wolf BC, Balogh K, Federman M 1985 Adrenal pheochromocytoma: a clinicopathologic review of 60 cases. Hum Pathol 16:580–589[Medline]
  24. Schlumberger M, Gicquel C, Lumbroso J, Tenenbaum F, Comoy E, Bosq J, Fonseca E, Ghillani PP, Aubert B, Travagli JP 1992 Malignant pheochromocytoma: clinical, biological, histologic and therapeutic data in a series of 20 patients with distant metastases. J Endocrinol Invest 15:631–642[Medline]
  25. Scott HWJ, Reynolds V, Green N, Page D, Oates JA, Robertson D, Roberts S 1982 Clinical experience with malignant pheochromocytomas. Surg Gynecol Obstet 154:801–818[Medline]
  26. Thompson LD 2002 Pheochromocytoma of the Adrenal gland Scaled Score (PASS) to separate benign from malignant neoplasms: a clinicopathologic and immunophenotypic study of 100 cases. Am J Surg Pathol 26:551–566[CrossRef][Medline]
  27. van der Harst E, Bruining HA, Jaap Bonjer H, van der Ham F, Dinjens WN, Lamberts SW, de Herder WW, Koper JW, Stijnen T, Proye C, Lecomte-Houcke M, Bosman FT, de Krijger RR 2000 Proliferative index in phaeochromocytomas: does it predict the occurrence of metastases? J Pathol 191:175–180[CrossRef][Medline]
  28. Pommier RF, Vetto JT, Billingsly K, Woltering EA, Brennan MF 1993 Comparison of adrenal and extraadrenal pheochromocytomas. Surgery 114:1160–1165[Medline]
  29. Glodny B, Winde G, Herwig R, Meier A, Kuhle C, Cromme S, Vetter H 2001 Clinical differences between benign and malignant pheochromocytomas. Endocr J 48:151–159[Medline]
  30. Pomares FJ, Canas R, Rodriguez JM, Hernandez AM, Parrilla P, Tebar FJ 1998 Differences between sporadic and multiple endocrine neoplasia type 2A phaeochromocytoma. Clin Endocrinol (Oxf) 48:195–200[CrossRef][Medline]
  31. Lairmore TC, Ball DW, Baylin SB, Wells SA 1993 Management of pheochromocytomas in patients with multiple endocrine neoplasia type 2 syndromes. Ann Surg 217:595–603[Medline]
  32. Proye CAG, Vix M, Jansson S, Tisell LE, Dralle H, Hiller W 1994 The pheochromocytoma: a benign, intra-adrenal, hypertensive, sporadic unilateral tumor. Does it exist? World J Surg 18:467–472[Medline]
  33. O’Riordain DS, Young Jr WF, Grant CS, Carney JA, van Heerden JA 1996 Clinical spectrum and outcome of functional extraadrenal paraganglioma. World J Surg 20:916–921[CrossRef][Medline]
  34. Shapiro B, Gross MD, Shulkin B 2001 Radioisotope diagnosis and therapy of malignant pheochromocytoma. Trends Endocrinol Metab 12:469–475[CrossRef][Medline]
  35. Pacak K, Goldstein DS, Doppman JL, Shulkin BL, Udelsman R, Eisenhofer G 2001 A "pheo" lurks: novel approaches for locating occult pheochromocytoma. J Clin Endocrinol Metab 86:3641–3646[Abstract/Free Full Text]
  36. Pacak K, Linehan WM, Eisenhofer G, Walther MM, Goldstein DS 2001 Recent advances in genetics, diagnosis, localization and treatment of pheochromocytoma. Ann Intern Med 134:315–329[Abstract/Free Full Text]
  37. Trampal C, Hengler H, Juhlin C, Bergstrom M, Langstrom B 2002 Detection of pheochromocytoma using 11C-hydroxyephedrine-PET. Radiology 225(Suppl):425
  38. Hoegerle S, Nitzsche E, Altehoefer C, Ghanem N, Manz T, Brink I, Reincke M, Moser E, Neumann HPH 2002 Pheochromocytomas: detection with 18F DOPA whole-body PET: initial results. Radiology 222:507–512[Abstract/Free Full Text]
  39. Glowniak JV, Kilty JE, Amara SG, Hoffman BJ, Turner FE 1993 Evaluation of metaiodobenzylguanidine uptake by the norepinephrine, dopamine and serotonin transporters. J Nucl Med 34:1140–1146[Abstract]
  40. Gourgiotis L, Sarlis NJ, Reynolds JC, VanWaes C, Merino MJ, Pacak K 2003 Localization of medullary thyroid carcinoma metastasis in a multiple endocrine neoplasia type 2A patient by 6-[18F]-fluorodopamine positron emission tomography. J Clin Endocrinol Metab 88:637–641[Abstract/Free Full Text]
  41. Chatal JF, Le Bodic MF, Kraeber-Bodere F, Rousseau C, Resche I 2000 Nuclear medicine applications for neuroendocrine tumors. World J Surg 24:1285–1289[CrossRef]
  42. Houben K, Dardashti K, Howard BD 1994 PC12 variants deficient in norepinephrine transporter mRNA have wild type activities of several other related transporters. Neurochem Res 19:743–751[Medline]
  43. Ramachandran B, Houben K, Rozenberg YY, Haigh JR, Varpetian A, Howard BD 1993 Differential expression of transporters for norepinephrine and glutamate in wild type, variant, and WNT1-expressing PC12 cells. J Biol Chem 268:23891–23897[Abstract/Free Full Text]
  44. Hofland LJ, Liu Q, Van Koetsveld PM, Zuijderwijk J, Van Der Ham F, de Krijger RR, Schonbrunn A, Lamberts SW 1999 Immunohistochemical detection of somatostatin receptor subtypes sst1 and sst2A in human somatostatin receptor positive tumors. J Clin Endocrinol Metab 84:775–780[Abstract/Free Full Text]
  45. Virgolini I, Leimer M, Handmaker H, Lastoria S, Bischof C, Muto P, Pangerl T, Gludovacz D, Peck-Radosavljevic M, Lister-James J, Hamilton G, Kaserer K, Valent P, Dean R 1998 Somatostatin receptor subtype specificity and in vivo binding of a novel tumor tracer99mTc-P829. Cancer Res 58:1850–1859[Abstract]
  46. Reubi JC, Wasser B, Khoshla S, Kvols L, Krenning E, Lamberts SW 1992 In vitro and in vivo detection of somatostatin receptors in pheochromocytomas and paragangliomas. J Clin Endocrinol Metab 74:1082–1089[Abstract]
  47. Epelbaum J, Bertherat J, Prevost G, Kordon C, Meyerhof W, Wulfsen I, Richter D, Plouin PF 1995 Molecular and pharmacological characterization of somatostatin receptor subtypes in adrenal, extraadrenal, and malignant pheochromocytomas. J Clin Endocrinol Metab 80:1837–1844[Abstract]
  48. Lenders JWM, Willemsen JJ, Beissel T, Kloppenborg PWC, Thien T, Benrad TJ 1992 Value of the plasma norepinephrine/3,4-dihydroxyphenylglycol ratio for the diagnosis of pheochromoctyoma. Am J Med 92:147–152[Medline]
  49. Lenders JW, Pacak K, Walther MM, Linehan WM, Mannelli M, Friberg P, Keiser HR, Goldstein DS, Eisenhofer G 2002 Biochemical diagnosis of pheochromocytoma: which test is best? JAMA 287:1427–1434[Abstract/Free Full Text]
  50. Eisenhofer G 2003 Editorial: biochemical diagnosis of pheochromocytoma–is it time to switch to plasma-free metanephrines? J Clin Endocrinol Metab 88:550–552[Free Full Text]
  51. Rotker J, Oberpennig F, Scheld HH, Hertle L, Knichwitz G, Hammel D 1996 Pheochromocytomas with extension into central vascular structures. Ann Thorac Surg 61:222–224[Abstract/Free Full Text]
  52. Piedrola G, Lopez E, Rueda MD, Lopez R, Serrano J, Sancho M 1997 Malignant pheochromocytoma of the bladder: current controversies. Eur Urol 31:122–125[Medline]
  53. Tato A, Orte L, Diz P, Quereda C, Ortuno J 1997 Malignant pheochromocytoma, still a therapeutic challenge. Am J Hypertens 10:479–481[Medline]
  54. Maier W, Marangos N, Laszig R 1999 Paraganglioma as a systemic syndrome: pitfalls and strategies. J Laryngol Otol 113:978–982[Medline]
  55. Keiser HR 2001 Pheochromocytoma and related tumors. In: DeGroot LJ, Jameson JL, eds. Endocrinology, 4th Ed. Philadelphia: Saunders; 1862–1883
  56. Hamilton BP, Landsberg L, Levine RJ 1978 Measurement of urinary epinephrine in screening for pheochromocytoma in multiple endocrine neoplasia type II. Am J Med 65:1027–1032[Medline]
  57. Mayo-Smith WW, Boland GW, Noto RB, Lee MJ 2001 State of the art adrenal imaging. Radiographics 21:995–1012[Abstract/Free Full Text]
  58. Quint LE, Glazer GM, Francis IR, Shapiro B, Chenevert TL 1987 Pheochromocytoma and paraganglioma: comparison of MR imaging with CT and I-131 MIBG scintigraphy. Radiology 165:89–93[Abstract]
  59. Ling D, Lee JKT 1989 The adrenals. In: Lee JKT, Sagel SS, Stanley RJ, eds. Computed body tomography with MRI correlation, 2nd Ed. New York: Raven Press; 827–849
  60. Boland GW, Lee MJ, Gazelle GS, Halpern EF, McNicholas MM, Mueller PR 1998 Characterization of adrenal masses using unenhanced CT: an analysis of the CT literature. AJR Am J Roentgenol 171:201–204[Abstract]
  61. Dunnick NR, Korobkin M 2002 Imaging of adrenal incidentalomas: current status. AJR Am J Roentgenol 179:559–568[Free Full Text]
  62. Korobkin M, Brodeur FJ, Yutzy GG, Francis IR, Quint LE, Dunnick NR, Kazerooni EA 1996 Differentiation of adrenal adenomas from nonadenomas using CT attenuation values. AJR Am J Roentgenol 166:531–536[Abstract]
  63. Caoili EM, Korobkin M, Francis IR, Cohan RH, Platt JF, Dunnick NR, Raghupathi KI 2002 Adrenal masses: characterization with combined unenhanced and delayed enhanced CT. Radiology 222:629–633[Abstract/Free Full Text]
  64. Sohaib SAA, Bomanji J, Evanson J, Reznek RH 2001 Imaging of the endocrine system. In: Grainger R, Allison D, Adam A, Dixon A, eds. Diagnostic radiology: a textbook of medical imaging, 4th Ed. London: Churchill Livingston; 1367–1399
  65. Dacie JE, White FE 1993 Radiology of endocrine disease. In: Besser GM, Thorner MO, eds. Atlas of endocrine imaging. London: Wolfe; 1–78
  66. Mori S, Okura T, Kitami Y, Takata Y, Nakamura M, Watanabe S, Iwata T, Hiwada K 2002 A case of metastatic extra-adrenal pheochromocytoma 12 years after surgery. Hypertens Res 25:141–144[CrossRef][Medline]
  67. Bender BU, Altehofer C, Januszewicz A, Gartner R, Schmidt H, Hoffmann MM, Heidemann PH, Neumann HP 1997 Functioning thoracic paraganglioma: association with von Hippel-Lindau syndrome. J Clin Endocrinol Metab 82:3356–3360[Abstract/Free Full Text]
  68. Braedel HU, Lindinger A, Berberich R, Schindler E, Crisp-Lindgren N 1986 Multiple extra-adrenal and thoracic pheochromocytomas. Urology 28:95–99[Medline]
  69. Shin MS, Gupta KL, Ho KJ 1986 Thoracic pheochromocytoma: computerized tomographic characteristics. South Med J 79:244–245[Medline]
  70. Shirkhoda A, Wallace S 1984 Computed tomography of juxtacardiac pheochromocytoma. J Comput Tomogr 8:207–209[Medline]
  71. Peppercorn PD, Reznek RH 1997 State-of-the-art CT and MRI of the adrenal gland. Eur Radiol 6:822–836[CrossRef]
  72. Jalil ND, Pattou FN, Combemale F, Chapuis Y, Henry JF, Peix JL, Proye CA 1998 Effectiveness and limits of preoperative imaging studies for the localisation of pheochromocytomas and paragangliomas: a review of 282 cases. French Association of Surgery (AFC), and The French Association of Endocrine Surgeons (AFCE). Eur J Surg 164:23–28[Medline]
  73. Boland GW, Lee MJ 1995 Magnetic resonance imaging of the adrenal gland. Crit Rev Diagn Imaging 36:115–174[Medline]
  74. Francis IR, Korobkin M 1996 Pheochromocytoma. Radiol Clin North Am 34:1101–1112[Medline]
  75. Maurea S, Cuocolo A, Reynolds JC, Tumeh SS, Begley MG, Linehan WM, Norton JA, Walther MM, Keiser HR, Neumann RD 1993 Iodine-131-metaiodobenzylguanidine scintigraphy in preoperative and postoperative evaluation of paragangliomas: comparison with CT and MRI. J Nucl Med 34:173–179[Abstract]
  76. Mannelli M, Ianni L, Cilotti A, Conti A 1999 Pheochromocytoma in Italy: a multicentric retrospective study. Eur J Endocrinol 142:619–624
  77. Maurea S, Cuocolo A, Reynolds JC, Neumann RD, Salvatore M 1996 Diagnostic imaging in patients with paragangliomas. Computed tomography, magnetic resonance and MIBG scintigraphy comparison. Q J Nucl Med 40:365–371[Medline]
  78. Berglund AS, Hulthen UL, Manhem P, Thorsson O, Wollmer P, Tornquist C 2001 Metaiodobenzylguanidine (MIBG) scintigraphy and computed tomography (CT) in clinical practice. Primary and secondary evaluation for localization of phaeochromocytomas. J Intern Med 249:247–251[CrossRef][Medline]
  79. Peplinski GR, Norton JA 1994 The predictive value of diagnostic tests for pheochromocytoma. Surgery 116:1101–1110[Medline]
  80. Korobkin M, Brodeur FJ, Francis IR, Quint LE, Dunnick NR, Londy F 1998 CT time-attenuation washout curves of adrenal adenomas and nonadenomas. AJR Am J Roentgenol 170:747–752[Abstract]
  81. Lauer UA, Klemm T, Graf H, Duda S, Claussen CD, Schick F 2002 Minimizing artefacts of metallic instruments and implants in MRI. Biomed Technol 47(Suppl 1):455–457
  82. McCarty M, Gedroyc WM 1993 Surgical clip artefact mimicking arterial stenosis: a problem with magnetic resonance angiography. Clin Radiol 48:232–235[Medline]
  83. Reif MC, Hanto DW, Moulton JS, Alspaugh JP, Bejarano P 1996 Primary hepatic pheochromocytoma? Am J Hypertens 9:1040–1043[CrossRef][Medline]
  84. Velchik MG, Alavi A, Kressel HY, Engelman K 1989 Localization of pheochromocytoma: MIGB, CT, and MRI correlation. J Nucl Med 30:328–336[Abstract]
  85. Mukherjee JJ, Peppercorn PD, Reznek RH, Patel V, Kaltsas G, Besser M, Grossman AB 1997 Pheochromocytoma: effect of nonionic contrast medium in CT on circulating catecholamine levels. Radiology 202:227–231[Abstract]
  86. Raisanen J, Shapiro B, Glazer GM, Desai S, Sisson JC 1984 Plasma catecholamines in pheochromocytoma: effect of urographic contrast media. AJR Am J Roentgenol 143:43–46[Medline]
  87. Witteles RM, Kaplan EL, Roizen MF 2000 Sensitivity of diagnostic and localization tests for pheochromocytoma in clinical practice. Arch Intern Med 160:2521–2524[Abstract/Free Full Text]
  88. Schmedtje JFJ, Sax S, Pool JL, Goldfarb RA, Nelson EB 1987 Localization of ectopic pheochromocytomas by magnetic resonance imaging. Am J Med 83:770–772[Medline]
  89. Reinig JW, Stutley JE, Leonhardt CM, Spicer KM, Margolis M, Caldwell CB 1994 Differentiation of adrenal masses with MR imaging: comparison of techniques. Radiology 192:41–46[Abstract]
  90. Mitchell DG 1992 Chemical shift magnetic resonance imaging: applications in the abdomen and pelvis. Top Magn Reson Imaging 4:46–63[Medline]
  91. Tsushima Y, Ishizaka H, Matsumoto M 1993 Adrenal masses: differentiation with chemical shift, fast low-angle shot MR imaging. Radiology 186:705–709[Abstract]
  92. Ichikawa T, Ohtomo K, Uchiyama G, Koizumi K, Monzawa S, Oba H, Nogata Y, Kachi K, Toyama K, Yamaguchi M 1994 Adrenal adenomas: characteristic hyperintense rim sign on fat-saturated spin-echo MR images. Radiology 193:247–250[Abstract]
  93. Bilbey JH, McLoughlin RF, Kurkjian PS, Wilkins GE, Chan NH, Schmidt N, Singer J 1995 MR imaging of adrenal masses: value of chemical-shift imaging for distinguishing adenomas from other tumors. AJR Am J Roentgenol 164:637–642[Abstract]
  94. Mitchell DG, Crovello M, Matteucci T, Petersen RO, Miettinen MM 1992 Benign adrenocortical masses: diagnosis with chemical shift MR imaging. Radiology 185:345–351[Abstract]
  95. Namimoto T, Yamashita Y, Mitsuzaki K, Nakayama Y, Makita O, Kadota M, Takahashi M 2001 Adrenal masses: quantification of fat content with double-echo chemical shift in-phase and opposed-phase FLASH MR images for differentiation of adrenal adenomas. Radiology 218:642–646[Abstract/Free Full Text]
  96. Fink IJ, Reinig JW, Dwyer AJ, Doppman JL, Linehan WM, Keiser HR 1985 MR imaging of pheochromocytomas. J Comput Assist Tomogr 9:454–458[Medline]
  97. Chang A, Glazer HS, Lee JKT, Ling D, Heiken JP 1987 Adrenal gland: MRI imaging. Radiology 163:123–128[Abstract]
  98. Varghese JC, Hahn PF, Papanicolaou N, Mayo-Smith WW, Gaa JA, Lee MJ 1997 MR differentiation of phaeochromocytoma from other adrenal lesions based on qualitative analysis of T2 relaxation times. Clin Radiol 52:603–606[Medline]
  99. Prager G, Heinz-Peer G, Passler C, Kaczirek K, Schindl M, Scheuba C, Vierhapper H, Niederle B 2002 Can dynamic gadolinium-enhanced magnetic resonance imaging with chemical shift studies predict the status of adrenal masses? World J Surg 26:958–964[CrossRef][Medline]
  100. Baker ME, Blinder R, Spritzer C, Leight GS, Herfkens RJ, Dunnick NR 1989 MR evaluation of adrenal masses at 1.5 T. AJR Am J Roentgenol 153:307–312[Medline]
  101. Krestin GP, Steinbrich W, Friedmann G 1989 Adrenal masses: evaluation with fast gradient-echo MR imaging and Gd-DTPA-enhanced dynamic studies. Radiology 171:675–680[Abstract]
  102. Lee MJ, Mayo-Smith WW, Hahn PF, Goldberg MA, Boland GW, Saini S, Papanicolaou N 1994 State-of-the-art MR imaging of the adrenal gland. Radiographics 14:1015–1029[Abstract]
  103. Honigschnabl S, Gallo S, Niederle B, Prager G, Kaserer K, Lechner G, Heinz-Peer G 2002 How accurate is MR imaging in characterisation of adrenal masses: update of a long-term study. Eur J Radiol 41:113–122[CrossRef][Medline]
  104. Aravot DJ, Banner NR, Cantor AM, Theodoropoulos S, Yacoub MH 1992 Location, localization and surgical treatment of cardiac pheochromocytoma. Am J Cardiol 69:283–285[Medline]
  105. Shellock FG, Kanal E 1999 Safety of magnetic resonance imaging contrast agents. J Magn Reson Imaging 10:477–484[CrossRef][Medline]
  106. Runge VM 2000 Safety of approved MR contrast media for intravenous injection. J Magn Reson Imaging 12:205–213[CrossRef][Medline]
  107. Runge VM 2001 Safety of magnetic resonance contrast media. Top Magn Reson Imaging 12:309–314[CrossRef][Medline]
  108. Ross JH 2000 Pheochromocytoma. Special considerations in children. Urol Clin North Am 27:393–402[Medline]
  109. Rackley R, Lorig R, Goldfarb D, Kay R 1994 Magnetic resonance imaging of pelvic tumors in children. J Urol 151:449–459[Medline]
  110. Gooding GA 1993 Adrenal, pancreatic, and scrotal ultrasound in endocrine disease. Radiol Clin North Am 31:1069–1083[Medline]
  111. Lucon AM, Pereira MA, Mendonca BB, Halpern A, Wajchenbeg BL, Arap S 1997 Pheochromocytoma: study of 50 cases. J Urol 157:1208–1212[Medline]
  112. Abrams HL, Siegelman SS, Adams DF, Sanders R, Finberg HJ, Hessel SJ, McNeil BJ 1982 Computed tomography versus ultrasound of the adrenal gland: a prospective study. Radiology 143:121–128[Abstract]
  113. Schwerk WB, Gorg C, Gorg K, Restrepo IK 1994 Adrenal pheochromocytomas: a broad spectrum of sonographic presentation. J Ultrasound Med 13:517–521[Abstract]
  114. Freier DT, Thompson NW 1993 Pheochromocytoma and pregnancy: the epitome of high risk. Surgery 114:1148–1152[Medline]
  115. Becker G, Jockenhovel F, Bauer R, Lederbogen S, Lange R, Reinwein D 1992 Cervical pheochromocytoma: a rare localization and a difficult diagnosis. J Endocrinol Invest 15:767–770[Medline]
  116. Thompson GB, Young Jr WF 2003 Adrenal incidentaloma. Curr Opin Oncol 15:84–90[CrossRef][Medline]
  117. Angeli A, Terzolo M 2002 Adrenal incidentaloma: a modern disease with old complications. J Clin Endocrinol Metab 87:4869–4871[Free Full Text]
  118. Wafelman AR, Hoefnagel CA, Maessen HJM, Maes RAA, Beijnen JH 1997 Renal excretion of iodine-131 labelled meta-iodobenzylguanidine and metabolites after therapeutic doses in patients suffering from different neural crest-derived tumours. Eur J Nucl Med 24:544–552[CrossRef][Medline]
  119. Krenning EP, Bakker WH, Kooij PP, Breeman WA, Oei HY, de Jong M, Reubi JC, Visser TJ, Bruns C, Kwekkeboom DJ 1992 Somatostatin receptor scintigraphy with indium-111-DTPA-D-Phe-1-octreotide in man: metabolism, dosimetry and comparison with iodine-123-Tyr-3-octreotide. Eur J Nucl Med 33:652–658
  120. Bajc M, Palmer J, Ohlsson T, Edenbrandt L 1994 Distribution and dosimetry of 111In DTPA-D-Phe-octreotide in man assessed by whole body scintigraphy. Acta Radiol 35:53–57[Medline]
  121. Arnberg H, Westlin JE, Husin S, Nilsson S 1993 Distribution and elimination of the somatostatin analogue (111In-DTPA-D-Phe1)-octreotide (OctreoScan111). Acta Oncol 32:177–182[Medline]
  122. Mozley PD, Kim CK, Moshin J, Gosfield E, Alavi A 1994 The efficacy of iodine-123-MIBG as a screening test for pheochromocytoma. J Nucl Med 35:1138–1144[Abstract]
  123. Behr TM, Behe M, Becker W 1999 Diagnostic applications of radiolabeled peptides in nuclear endocrinology. Q J Nucl Med 43:268–280[Medline]
  124. Clerc J, Mardon K, Galoons H, Loc’h C, Lumbroso J, Merlet P, Zhu J, Jeusset J, Syrota A, Fragu P 1995 Assessing intratumor distribution and uptake with MIBG versus MIBG imaging and targeting xenografted PC-12 pheochromocytoma cell line. J Nucl Med 36:859–866[Abstract]
  125. Solanki KK, Bomanji J, Moyes J, Mather SJ, Trainer PJ, Britton KE 1992 A pharmacological guide to medicines which interfere with the biodistribution of radiolabelled meta-iodobenzylguanidine (MIBG). Nucl Med Commun 13:513–521[Medline]
  126. Plowman PN 1997 Positive MIBG scanning at the time of relapse in neuroblastoma which was MIBG negative at diagnosis. Br J Radiol 70:969
  127. Huguet F, Fagret D, Caillet M, Piriou A, Besnard JC, Guilloteau D 1996 Interaction of metaiodobenzylguanidine with cardioactive drugs: an in vitro study. Eur J Nucl Med 23:546–549[Medline]
  128. Khafagi FA, Shapiro B, Fig LM, Mallette S, Sisson JC 1989 Labetalol reduces iodine-131 MIBG uptake by pheochromocytoma and normal tissues. J Nucl Med 30:481–489[Abstract]
  129. Swanson DP, Carey JE, Brown LE, Kline RC, Wieland DM, Thrall JH, Beierwaltes WH Human absorbed dose calculations for iodine-131 and iodine-123 labeled meta-iodobenzylguanidine (mIBG): a potential myocardial and adrenal medulla imaging agent. 3rd International Radiopharmaceutical Dosimetry Symposium, Rockville, MD, 1981, 213–224
  130. Lynn MD, Shapiro B, Sisson JC, Swanson DP, Mangner TJ, Wieland DM, Meyers LJ, Glowniak JV, Beierwaltes WH 1984 Portrayal of pheochromocytoma and normal human adrenal medulla by m-[123I] iodobenzylguanidine: concise communication. J Nucl Med 25:436–440[Abstract]
  131. Shapiro B, Gross MD 1987 Radiochemistry, biochemistry, and kinetics of 131I-metaiodobenzylguanidine (MIBG) and 123I-MIBG: clinical implications of the use of 123I-MIBG. Med Pediatr Oncol 15:170–177[Medline]
  132. Wafelman AR, Suchi R, Hoefnagel CA, Beijnen JH 1993 Radiochemical purity of iodine-131 labelled metaiodobenzylguanidine infusion fluids: a report from clinical practice. Eur J Nucl Med 20:614–616[Medline]
  133. Wafelman AR, Hoefnagel CA, Beijnen JH 1993 Radiochemical stability during infusion of 131I-labelled metaiodobenzylguanidine for therapeutic use. Nucl Med Commun 14:819–822[Medline]
  134. Ertl S, Deckart H, Blottner A, Tautz M 1987 Radiopharmacokinetics and radiation absorbed dose calculations from 131I-meta-iodobenzylguanidine (131I-MIBG). Nucl Med Commun 8:643–653[Medline]
  135. van Santen HM, de Kraker J, van Eck BL, de Vijlder JJ, Vulsma T 2002 High incidence of thyroid dysfunction despite prophylaxis with potassium iodide during 131I-meta-iodobenzylguanidine treatment in children with neuroblastoma. Cancer 94:2081–2089[CrossRef][Medline]
  136. Brans B, Monsieurs M, Laureys G, Kaufman JM, Thierens H, Dierckx RA 2002 Thyroidal uptake and radiation dose after repetitive I-131-MIBG treatments: influence of potassium iodide for thyroid blocking. Med Pediatr Oncol 38:41–46[CrossRef][Medline]
  137. Roelants V, Goulios C, Beckers C, Jamar F 1998 Iodine-131-MIBG scintigraphy in adults: interpretation revisited? J Nucl Med 39:1007–1012[Abstract]
  138. Morozumi T, Fukuchi K, Uehara T, Kusuoka H, Hori M, Nishimura T 1996 Abnormal iodine-123-MIBG images in healthy volunteers. J Nucl Med 37:1686–1688[Abstract]
  139. Franceschini R, Pecorale A, Chinol M, Calcagni ML, Servidei T, Riccardi R, Troncone L 1995 In vitro and in vivo studies with no-carrier added radioiodinated MIBG. Q J Nucl Med 39(Suppl 1):72–77
  140. Elgazzar AH, Gelfand MJ, Washburn LC, Clark J, Nagaraj N, Cummings D, Hughes J, Maxon HR 1995 I-123 MIBG scintigraphy in adults. A report of clinical experience. Clin Nucl Med 20:147–152[Medline]
  141. Nakajo M, Shapiro B, Copp J, Kalff V, Gross MD, Sisson JC, Beierwaltes WH 1983 The normal and abnormal distribution of the adrenomedullary imaging agent m-[I-131]iodobenzylguanidine (I-131 MIBG) in man: evaluation by scintigraphy. J Nucl Med 24:672–682[Abstract]
  142. Kline RC, Swanson DP, Wieland DM, Thrall JH, Gross MD, Pitt B, Beierwaltes WH 1981 Myocardial imaging in man with I-123 meta-iodobenzylguanidine. J Nucl Med 22:129–132[Abstract]
  143. Geatti O, Shapiro B, Shulkin B, Hutchinson R, Sisson JC 1988 Gastrointestinal iodine-131-meta-iodobenzylguanidine activity. Am J Physiol Imaging 3:188–191[Medline]
  144. Dwamena BA, Zempel S, Klopper JF, Van Heerden B, Wieland D, Shapiro B 1998 Brain uptake of iodine-131 metaiodobenzylguanidine following therapy of malignant pheochromocytoma. Clin Nucl Med 23:441–445[CrossRef][Medline]
  145. Hattner RS, Pounds TR, Matthay KK 1994 Normal cerebellar MIBG localization. Implications in the interpretation of delayed scans. Clin Nucl Med 19:985–988[Medline]
  146. Tytgat GA, van den Brug MD, Voute PA, Smets LA, Rutgers M 2002 Human megakaryocytes cultured in vitro accumulate serotonin but not meta-iodobenzylguanidine whereas platelets concentrate both. Exp Hematol 30:555–563[CrossRef][Medline]
  147. Tytgat GA, Voute PA, Takeuchi S, Miyoshi I, Rutgers M 1995 Meta-iodobenzylguanidine uptake in platelets, megakaryoblastic leukaemia cell lines MKPL-1 and CHRF-28–11 and erythroleukaemic cell line HEL. Eur J Cancer 31A:603–606
  148. Nakajo M, Shapiro B, Sisson JC, Swanson DP, Beierwaltes WH 1984 Salivary gland accumulation of meta-[131I]iodobenzylguanidine. J Nucl Med 25:2–6[Abstract]
  149. Sisson JC, Frager MS, Valk TW, Gross MD, Swanson DP, Wieland DM, Tobes MC, Beierwaltes WH, Thompson NW 1981 Scintigraphic localization of pheochromocytoma. N Engl J Med 305:12–17[Abstract]
  150. Lynn MD, Shapiro B, Sisson JC, Beierwaltes WH, Meyers LJ, Ackerman R, Mangner TJ 1985 Pheochromocytoma and the normal adrenal medulla: improved visualization with I-123 MIBG scintigraphy. Radiology 155:789–792[Abstract]
  151. Fujita A, Hyodoh H, Kawamura Y, Kanegae K, Furuse M, Kanazawa K 2000 Use of fusion images of I-131 metaiodobenzylguanidine, SPECT and magnetic resonance studies to identify a malignant pheochromocytoma. Clin Nucl Med 25:440–442[CrossRef][Medline]
  152. Sisson JC, Shulkin BL 1999 Nuclear medicine imaging of pheochromocytoma and neuroblastoma. Q J Nucl Med 43:217–223[Medline]
  153. Gelfand MJ, Elgazzar AH, Kriss VM, Masters PR, Golsch GJ 1994 Iodine-123-MIBG SPECT versus planar imaging in children with neural crest tumors. J Nucl Med 35:1753–1757[Abstract]
  154. Tsuchimochi S, Nakajo M, Nakabeppu Y, Tani A 1997 Metastatic pulmonary pheochromocytomas: positive I-123 MIBG SPECT with negative I-131 MIBG and equivocal I-123 MIBG planar imaging. Clin Nucl Med 22:687–690[CrossRef][Medline]
  155. Shulkin BL, Shapiro B, Francis IR, Dorr R, Shen SW, Sisson JC 1986 Primary extra-adrenal pheochromocytoma: positive I-123 MIBG imaging with negative I-131 MIBG imaging. Clin Nucl Med 11:851–854[Medline]
  156. van der Harst E, de Herder WW, Bruining HA, Bonjer HJ, de Krijger RR, Lamberts SW, van de Meiracker AH, Boomsma F, Stijnen T, Krenning EP, Bosman FT, Kwekkeboom DJ 2001 [123I]Metaiodobenzylguanidine and [111In]octreotide uptake in benign and malignant pheochromocytomas. J Clin Endocrinol Metab 86:685–693[Abstract/Free Full Text]
  157. Bravo EL 1994 Evolving concepts in the pathophysiology, diagnosis and treatment of pheochromocytoma. Endocr Rev 15:356–358[Medline]
  158. Nielsen JT, Nielsen BV, Rehling M 1996 Location of adrenal medullary pheochromocytoma by I-123 metaiodobenzylguanidine SPECT. Clin Nucl Med 21:695–699[CrossRef][Medline]
  159. Maurea S, Klain M, Caraco C, Ziviello M, Salvatore M 2002 Diagnostic accuracy of radionuclide imaging using 131I nor-cholesterol or meta-iodobenzylguanidine in patients with hypersecreting or non-hypersecreting adrenal tumours. Nucl Med Commun 23:951–960[CrossRef][Medline]
  160. Berchtenbreiter C, Bruning R, Auernhammer A, Reiser M 1999 Misleading diagnosis of retroperitoneal actinomycosis. Eur Radiol 9:1869–1872[CrossRef][Medline]
  161. Letizia C, De Toma G, Massa R, Corsi A, Caliumi C, Subioli S, D’Erasmo E 1998 False-positive diagnosis of adrenal pheochromocytoma on iodine-123-MIBG scan. J Endocrinol Invest 21:779–783[Medline]
  162. Bathmann J, Neumann HP, Sigmund G, Moser E 1994 False-positive diagnosis of a pheochromocytoma with I-123 metaiodobenzylguanidine. Clin Nucl Med 19:221–223[Medline]
  163. Furuta N, Kiyota H, Yoshigoe F, Hasegawa N, Ohishi Y 1999 Diagnosis of pheochromocytoma using [123I]- compared with [131I]-metaiodobenzylguanidine scintigraphy. Int J Urol 6:119–124[CrossRef][Medline]
  164. Eisenhofer G, Pacak K, Goldstein DS, Chen C, Shulkin B 2000 123I-MIBG scintigraphy of catecholamine systems: impediments to applications in clinical medicine. Eur J Nucl Med 27:611–612
  165. Kaltsas G, Korbonits M, Heintz E, Mukherjee JJ, Jenkins PJ, Chew SL, Reznek R, Monson JP, Besser GM, Foley R, Britton KE, Grossman AB 2001 Comparison of somatostatin analog and meta-iodobenzylguanidine radionuclides in the diagnosis and localization of advanced neuroendocrine tumors. J Clin Endocrinol Metab 86:895–902[Abstract/Free Full Text]
  166. Shulkin BL, Wienland DM, Shapiro B, Sisson JC 1995 PET epinephrine studies of pheochromocytoma. J Nucl Med 36:229P[Abstract]
  167. Shulkin BL, Wieland DM, Schwaiger M, Thompson NW, Francis IR, Haka MS, Rosenspire KC, Shapiro B, Sisson JC, Kuh IDE 1992 PET scanning with hydroxyephedrine: an approach to the localization of pheochromocytoma. J Nucl Med 33:1125–1131[Abstract]
  168. Shulkin BL, Thompson NW, Shapiro B, Francis IR, Sisson JC 1999 Pheochromocytomas: imaging with 2-[fluorine-18]fluoro-2-deoxy-D-glucose PET. Radiology 212:35–41[Abstract/Free Full Text]
  169. Taniguchi K, Ishizu K, Torizuka T, Hasegawa S, Okawada T, Ozawa T, Iino K, Taniguchi M, Ikematsu Y, Nishiwaki Y, Kida H, Waki S, Uchimura M 2001 Metastases of predominantly dopamine-secreting phaeochromocytoma that did not accumulate meta-iodobenzylguanidine: imaging with whole body positron emission tomography using 18F-labelled deoxyglucose. Eur J Surg 167:866–870[CrossRef][Medline]
  170. Hoegerle S, Ghanem N, Altehoefer C, Schipper J, Brink I, Moser E, Neumann HP 2003 18F-DOPA positron emission tomography for the detection of glomus tumours. Eur J Nucl Med Mol Imaging 30:689–694[Medline]
  171. Hovevey-Sion D, Eisenhofer G, Kopin IJ, Kirk KL, Chang PC, Szemeredi K, Goldstein DS 1990 Metabolic fate of injected radiolabelled dopamine and 2-fluorodopamine in rats. Neuropharmacology 29:881–887[CrossRef][Medline]
  172. Pacak K, Eisenhofer G, Carrasquillo JA, Chen CC, Li ST, Goldstein DS 2001 6-[18F]fluorodopamine positron emission tomographic (PET) scanning for diagnostic localization of pheochromocytoma. Hypertension 38:6–8[Abstract/Free Full Text]
  173. Ilias I, Yu J, Goldstein D, Eisenhofer G, Chen C, Carrasquillo J, Padmanabhan H, Perera S, Pacak K 6-[18F]-fluorodopamine positron emission tomography versus [131I]-metaiodobenzylguanidine scintigraphy in the evaluation of patients with pheochromocytoma [Abstract P3–511]. 84th Annual Meeting of The Endocrine Society, San Fransisco, CA, 2002, 611
  174. Ilias I, Yu J, Carrasquillo J, Chen C, Eisenhofer G, Whatley M, McElroy B, Pacak K 2003 Superiority of 6-[18F]-fluorodopamine positron emission tomography versus [131I]-metaiodobenzylguanidine scintigraphy in the localization of metastatic pheochromocytoma. J Clin Endocrinol Metab 88:4083–4087[Abstract/Free Full Text]
  175. Goldstein DS, Holmes C 1997 Metabolic fate of the sympathoneural imaging agent 6-[18F]fluorodopamine in humans. Clin Exp Hypertens 19:155–161[Medline]
  176. Goldstein D, Coronado L, Kopin I 1994 6-[Fluorine-18]fluorodopamine pharmacokinetics and dosimetry in humans. J Nucl Med 35:964–973[Abstract]
  177. Breeman WA, De Jong M, Kwekkeboom DJ, Valkema R, Bakker WH, Kooij PPM, Visser TJ, Krenning EP 2001 Somatostatin receptor-mediated imaging and therapy: basic science, current knowledge, limitations and future perspectives. Eur J Nucl Med 28:1412–1429
  178. Reubi JC 2003 Peptide receptors as molecular targets for cancer diagnosis and therapy. Endocr Rev 24:389–427[Abstract/Free Full Text]
  179. Krenning EP, Kwekkeboom DJ, Pawels S, Kvols LK, Reubi JC 1995 Somatostatin receptor scintigraphy. In: Freeman LM, ed. Nuclear medicine annual 1995. New York: Raven Press; 242–244
  180. Prevost G, Veber N, Viollet C, Roubert V, Roubert P, Benard J, Eden P 1996 Somatostatin-14 mainly binds the somatostatin receptor subtype 2 in human neuroblastoma tumors. Neuroendocrinology 63:188–197[Medline]
  181. Hofland LJ, Lamberts SWJ 2001 Somatostatin receptor subtype expression in human tumors. Ann Oncol 12(Suppl 2):S31–S36
  182. Lamberts SW, Krenning EP, Reubi JC 1991 The role of somatostatin and its analogs in the diagnosis and treatment of tumors. Endocr Rev 12:450–482[Medline]
  183. Krausz Y, Shibley N, De Jong RB, Yaffe S, Glaser B 1994 Gallbladder visualization with In-111 labeled octreotide. Clin Nucl Med 19:133–135[Medline]
  184. Vanhagen PM, Krenning EP, Reubi J, Kwekkeboom DJ, Bakker WH, Mulder AH, Laissue I, Hoogstede HC, Lamberts SW 1994 Somatostatin analogue scintigraphy in granulomatous diseases. Eur J Nucl Med 21:497–502[Medline]
  185. Oyen WJ, Boerman OC, Claessens RA, van der Meer JW, Corstens FH 1994 Is somatostatin receptor scintigraphy suited to detection of acute infectious disease? Nucl Med Commun 15:289–293[Medline]
  186. Krenning EP, Kwekkekeboom DJ, Bakker WH, Breeman WA, Kooij PP, Oei HY, van Hagen M, Postema PT, de Jong M, Reubi JC 1993 Somatostatin receptor scintigraphy with [111In-DTPA-D-phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients. Eur J Nucl Med 20:716–731[Medline]
  187. Lauriero F, Rubini G, D’Addabo F, Rubini D, Schettini F, D’Addabo A 1995 I-131 MIBG scintigraphy of neuroectodermal tumors. Comparison between I-131 MIBG and In-DTPA-octreotide. Clin Nucl Med 20:243–249[Medline]
  188. Limouris GS, Giannakopoulos V, Stavraka A, Toubanakis N, Vlahos L 1997 Comparison of In-111 pentetreotide, Tc-99m (V)DMSA and I-123 MIBG scintimaging in neural crest tumors. Anticancer Res 17:1589–1592[Medline]
  189. Kopf D, Bockisch A, Steinert H, Hahn K, Beyer J, Neumann HP, Hensen J, Lehnert H 1997 Octreotide scintigraphy and catecholamine response to an octreotide challenge in malignant phaeochromocytoma. Clin Endocrinol (Oxf) 46:39–44[Medline]
  190. Lastoria S, Maurea S, Vergara E, Acampa W, Varrella P, Klain M, Muto P, Bernardy JD, Salvatore M 1995 Comparison of labeled MIBG and somatostatin analogs in imaging neuroendocrine tumors. Q J Nucl Med 39:145–149
  191. Tenenbaum F, Lumbroso J, Schlumberger M, Mure A, Plouin PF, Caillou B, Parmentier C 1995 Comparison of radiolabeled octreotide and meta-iodobenzylguanidine (MIBG) scintigraphy in malignant pheochromocytoma. J Nucl Med 36:1–6[Abstract]
  192. De Jong M, Bakker WH, Breeman WA, Bernard BF, Hofland LJ, Visser TJ, Srinivasan A, Schmidt M, Behe M, Macke HR, Krenning EP 1998 Pre-clinical comparison of [DTPA0] octreotide, [DTPA0, Tyr3] octreotide and [DOTA0, Tyr3] octreotide as carriers for somatostatin receptor-targeted scintigraphy and radionuclide therapy. Int J Cancer 75:406–411[CrossRef][Medline]
  193. de Jong M, Breeman WA, Bakker WH, Kooij PP, Bernard BF, Hofland LJ, Visser TJ, Srinivasan A, Schmidt MA, Erion JL, Bugaj JE, Macke HR, Krenning EP 1998 Comparison of 111In-labeled somatostatin analogues for tumor scintigraphy and radionuclide therapy. Cancer Res 58:437–441[Abstract]
  194. Jamar F, Barone R, Mathieu I, Walrand S, Labar D, Carlier P, De Camps J, Schran H, Chen T, Smith MC, Bouterfa H, Valkema R, Krenning EP, Kvols LK, Pauwels S 2003 86Y-DOTA0-D-Phe1-Tyr3-octreotide (SMT487): a phase 1 clinical study: pharmacokinetics, biodistribution and renal protective effect of different regimens of amino acid co-infusion. Eur J Nucl Med Mol Imaging 30:510–518[Medline]
  195. Manil L, Edeline V, Michon J, Neuenschwander S, Lequen H, Lavocat C, Zucker JM 1996 Could somatostatin scintigraphy be superior to MIBG scan in the staging of stage IVs neuroblastoma (Pepper’s syndrome)? Clin Nucl Med 21:530–533[CrossRef][Medline]
  196. Eisenhofer G, Goldstein DS, Walther MM, Friberg P, Lenders JWM, Keiser HR, Pacak K 2003 Biochemical diagnosis of pheochromocytoma: how to distinguish true- from false-positive test results. J Clin Endocrinol Metab 88:2656–2666[Abstract/Free Full Text]
  197. Manger WH 2003 In search of pheochromocytomas. J Clin Endocrinol Metab 88:4080–4082[Free Full Text]
  198. Rimmelin A, Hartheiser M, Gangi A, Welsch M, Jeung MY, Jaeck D, Tongio J, Dietemann JL 1996 Primary hepatic pheochromocytoma. Eur Radiol 6:82–85[Medline]
  199. Chen H, Doppman JL, Chrousos GP, Norton JA, Nieman LK, Udelsman R 1995 Adrenocorticotropic hormone-secreting pheochromocytomas: the exception to the rule. Surgery 118:988–994[Medline]
  200. Chew SL, Dacie JE, Reznek RH, Newbould EC, Sheaves R, Trainer PJ, Lowe DG, Shand WS, Hungerford J, Besser GM, Grossman AB 1994 Bilateral phaeochromocytomas in von Hippel-Lindau disease: diagnosis by adrenal vein sampling and catecholamine assay. Q J Med 87:49–54[Medline]
  201. O’Brien T, Young Jr WF, Davila DG, Scheithauer BW, Kovacs K, Horvath E, Vale W, van Heerden JA 1992 Cushing’s syndrome associated with ectopic production of corticotrophin-releasing hormone, corticotrophin and vasopressin by a phaeochromocytoma. Clin Endocrinol (Oxf) 37:460–467[Medline]
  202. Newbould EC, Ross GA, Dacie JE, Bouloux PM, Besser GM, Grossman A 1991 The use of venous catheterization in the diagnosis and localization of bilateral phaeochromocytomas. Clin Endocrinol (Oxf) 35:55–59[Medline]
  203. Pontremoli R, Borgonovo G, Ranise A, Garibotto G 1989 Multiple venous sampling for catecholamine assay in the diagnosis of malignant pheochromocytoma. J Endocrinol Invest 12:647–649[Medline]
  204. Koshida K, Nishikawa T, Ishida T, Naito K, Hisazumi H 1988 A clinical review of 30 pheochromocytoma patients. Hinyokika Kiyo 34:592–597[Medline]
  205. Collste P, Brismar B, Alveryd A, Bjorkhem I, Hardstedt C, Svensson L, Ostman J 1986 The catecholamine concentration in central veins of hypertensive patients–an aid not without problems in locating phaeochromocytoma. Acta Chir Scand 530(Suppl):67–71
  206. Miller JL, Immelman EJ, Roman TE, Mervis B 1983 Phaeochromocytoma of the urinary bladder localized by selective venous sampling and computed tomography. Postgrad Med J 59:533–535[Abstract]
  207. Manu P 1983 Venous sampling in locating a phaeochromocytoma. Br Med J (Clin Res Ed) 286:1825
  208. Allison DJ, Brown MJ, Jones DH, Timmis JB 1983 Role of venous sampling in locating a phaeochromocytoma. Br Med J (Clin Res Ed) 286:1122–1124[Medline]
  209. Fiorica V, Galloway DC, Males JL, Painton RP, Kem DC 1982 Epinephrine fraction of adrenal vein blood in pheochromocytoma. Am J Med Sci 284:9–15[Medline]
  210. Nobin A, Karp W, Lunderquist A, Rosengren E, Sanden G, Sundler F 1982 Localization of carcinoids and pheochromocytomas with vein catheterization and amine determination. Brain Res Bull 9:781–797[CrossRef][Medline]
  211. Dunnick NR, Doppman JL, Gill Jr JR, Strott CA, Keiser HR, Brennan MF 1982 Localization of functional adrenal tumors by computed tomography and venous sampling. Radiology 142:429–433[Abstract]
  212. Kadir S, Robinette C 1981 Accuracy of angiography in the localization of pheochromocytoma. J Urol 126:789–793[Medline]
  213. Bolli G, De Feo P, Compagnucci P, Cartechini MG, Samteusano F, Brunetti P 1981 Simultaneous central venous and arterial blood sampling for catecholamine assay in phaeochromocytoma. Lancet 2:526–527
  214. Jones DH, Allison DJ, Hamilton CA, Reid JL 1979 Selective venous sampling in the diagnosis and localization of phaeochromocytoma. Clin Endocrinol (Oxf) 10:179–186[Medline]