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Special Feature |
Pediatric and Reproductive Endocrinology Branch (I.I., J.Y., K.P.), National Institute of Child Health and Human Development; Nuclear Medicine Department (J.A.C., C.C.C., M.W.) and Nursing Department (B.M.), Warren Grant Magnuson Clinical Center; and Clinical Neurocardiology Section (G.E.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-1583
Address all correspondence and requests for reprints to: Karel Pacak, M.D., Ph.D., D.Sc., Chief, Unit on Clinical Neuroendocrinology, PREB, NICHD, NIH, Building 10 Room 9D42, 10 Center Drive, Bethesda, Maryland 20892. E-mail: karel{at}mail.nih.gov.
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Functional imaging methods are also used to localize PHEO. Metaiodobenzylguanidine (MIBG) has structural similarities to norepinephrine, enters sympathomedullary tissue via the noradrenergic transporter system (8), and is minimally metabolized. Scintigraphy with either [131I]- or [123I]-MIBG (the latter enabling better-quality imaging) has been used extensively as a first line nuclear imaging method in the work-up of patients with PHEO (8, 9, 10, 11). Currently, [123I]-MIBG scintigraphy is not widely used in the United States because of its limited availability. Somatostatin receptor scintigraphy with [111In]-pentetreotide has also been performed in patients with PHEO (12, 13, 14, 15). Additionally, positron emission tomography (PET) with [18F]-fluorodeoxyglucose (FDG) (16), [11C]-hydroxyephedrine (17), or [11C]-epinephrine (18) has also been used in these patients. However, these modalities have all been shown to have limited diagnostic yield because of their less-than-perfect sensitivity and/or specificity (7, 19, 20, 21). Moreover, MIBG and [111In]-pentetreotide scintigraphy have been shown to be negative in some cases of metastatic PHEO because of tumor dedifferentiation that results in the loss of the noradrenergic transporter system or somatostatin receptors (12, 13). Thus, in these patients, metastatic lesions may remain undetected.
Dopamine is a better substrate for the norepinephrine transporter than most other amines, including norepinephrine (22). Thus, a labeled analog of dopamine should be useful as a scintigraphic imaging agent. 6-[18F]-fluorodopamine ([18F]-DA), a sympathoneuronal imaging agent developed at NIH, is a positron-emitting analog of dopamine and a good substrate for both the plasma membrane and intracellular vesicular transporters in catecholamine-synthesizing cells (22). This results in a tissue-blood concentration ratio for [18F]-DA of more than 1000 and good visualization of these cells (23). Recent studies have suggested that [18F]-DA is an excellent agent for localization of PHEO, including metastatic lesions (5, 24, 25). The aim of the present study was to compare the diagnostic utility of [18F]-DA PET vs. [131I]-MIBG scintigraphy in patients with suspected or known metastatic PHEO.
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Subjects and Methods |
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At NIH, all patients underwent extensive biochemical testing (measured with in-house assays, as previously described) (26, 27, 28, 29). Imaging studies including CT, MRI, [18F]-DA PET scanning and [131I]-MIBG scintigraphy were also performed at NIH unless they had been performed elsewhere and no more than 3 months apart from the other imaging modalities. For the seven patients who had CT or MRI scans performed outside NIH, two required repeat imaging because the outside scans were felt to be suboptimal in quality. Three patients had [131I]-MIBG scans performed outside NIH, one of which was repeated.
CT from the neck to the pelvis was performed with a Hi Speed Advantage scanner (General Electric Medical Systems, Milwaukee, WI). Section thickness was 5 mm through the chest and upper abdomen to the adrenals and 10 mm through the lower abdomen. All sections were contiguous. A contrast agent was administered orally. Most studies were performed during a bolus (130 ml injected iv at 2 ml/sec) of nonionic water-soluble contrast. MRI from the neck to the pelvis was obtained with a 0.5-T scanner (Picker, Highland Heights, OH). T1-weighted spin-echo imaging was performed with a repetition time (TR) of 300 msec, echo time (TE) of 10 msec (TR/TE = 300/10), and eight excitations. T2-weighted spin-echo imaging was performed with TR/TE of 2000/80 and two excitations. Short inversion time inversion-recovery imaging was performed with a TR of 1600 msec, TE of 30 msec, inversion time of 100 msec, and four excitations. Images were obtained in the coronal and axial planes. For [131I]-MIBG scanning, patients were imaged approximately 24 and 48 h following iv administration of 0.5 mCi (18.5 MBq) [131I]-MIBG. To protect the thyroid from accumulation of free radioactive iodine, patients were instructed to take 100 mg of saturated solution of potassium iodide by mouth twice a day for 8 d, starting the night before MIBG administration. Scans were acquired on a dual-headed 
camera (ADAC Laboratories, Milpitas, CA) equipped with high-energy general-purpose collimators. Twenty-minute spot images of the skull to the midfemurs were obtained, with additional views of the lower extremities included as needed. On occasion, 72-h images were also obtained.
For PET scanning, the patients were studied fasting and were asked to avoid caffeine, tobacco, and alcohol for at least 12 h before the scan (to avoid any interference with the imaging process because caffeine is a weak adrenergic stimulant, and tobacco and alcohol are known to influence gastrointestinal motility). [18F]-DA (1.0 mCi; 37 MBq) in 10 ml of normal saline was infused over 3 min via an antecubital iv catheter. Attenuation-corrected images were obtained (from the neck to the pelvis in 13 patients and from the head to the midthighs in three patients, the latter being patients no. 2, 4, and 9), starting immediately after injection (15 min per position). [18F]-DA PET scanning was performed using an Advance scanner (General Electric) with a 15-cm field of view. Images where initially obtained in 3-dimensional mode (with filtered back-projection reconstruction algorithm; 11 studies) and later in two-dimensional mode (with an iterative reconstruction algorithm; seven studies). The duration of emission scanning was 8–15 min at each level. At least one transmission scan of 3- to 5-min duration was obtained at each level. Anatomic imaging studies were interpreted by radiologists who were not blinded to the results of [18F]-DA PET, [131I]-MIBG, or other patient information. [18F]-DA PET and [131I]-MIBG studies were each read by two nuclear medicine physicians (J.A.C. and C.C.C.) during separate reading sessions. These readers were blinded to the results of all other imaging modalities. Lesions were graded on a scale of 1–5 (1 = not PHEO, 2 = doubtful, 3 = equivocal, 4 = probable, 5 = definite PHEO). Lesions with scores of 4 and 5 were counted as positive findings. Discrepancies were resolved by consensus review of the modality in question.
Two patients were studied twice (no. 15 and 16). In these patients, all the imaging modalities were repeated after approximately 2 yr.
For sensitivity calculations, [18F]-DA PET and [131I]-MIBG scans were considered either positive or negative, regardless of the number of lesions seen.
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Results |
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Fifteen of 16 patients had findings on CT and/or MRI consistent with metastatic PHEO, but patient no. 4 had negative CT and MRI scans that showed only compensatory thickening of the left adrenal gland following a previously performed right adrenalectomy (Table 1
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Ten foci in four patients (no. 8–11) were visualized only on [131I]-MIBG scans. Nine of these 10 foci were in the head and/or lower extremities, which were not scanned in the [18F]-DA PET, CT, or MRI studies. Two patients (no. 8 and 10) had [131I]-MIBG lesions in the head, and patient no. 9 (who had a head to midthigh [18F]-DA PET scan) had foci of [131I]-MIBG uptake in the knees. In patient no. 11, [131I]-MIBG revealed an abdominal focus that was not seen with [18F]-DA PET, although other abdominal foci were detected with PET. CT/MRI did not reveal any abdominal lesions but were abnormal in the chest and pelvis.
Of the two patients who were studied twice, one (no. 15) had positive [18F]-DA PET and [131I]-MIBG studies that identified the same foci on both occasions. The other patient (no. 16) also had positive [18F]-DA PET and [131I]-MIBG studies on both occasions showing the same foci, although [18F]-DA PET also showed some additional foci, the number of which increased on the second scan.
In one patient (no. 4) in whom CT, MRI, and [131I]-MIBG scintigraphy were negative, the only positive imaging study was the [18F]-DA PET scan. This patient subsequently had a [123I]-MIBG study at another institution that confirmed the PET finding and eventually underwent surgery in which metastatic PHEO was found in the abdomen.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Among the imaging modalities used for PHEO, CT has a high sensitivity for detecting adrenal PHEO that approaches 98.9% (30, 31, 32), and MRI has an even higher sensitivity, approaching 100% (33, 34). However, sensitivity decreases to 90.9% or lower for both modalities in detecting extraadrenal, metastatic, or recurrent PHEO (7, 18, 30, 31, 32, 35, 36), or to 77% (CT) and 85% (MRI) when postoperative changes are present (24, 32). Although the specificity of MRI is superior to CT, it has been shown to be limited (approximately 50%) (21, 33). In contrast, [131I]-MIBG scanning offers excellent specificity (95%–100%) but suffers from imperfect sensitivity (approximately 77%) (10, 11, 12, 37). With [123I]-MIBG, however, the sensitivity for detecting PHEO is higher, reportedly approaching 90% (38). This is likely related to the higher administered dose and better imaging characteristics of 123I- vs. 131I-MIBG. Unfortunately, [123I]-MIBG scintigraphy is not widely used in the United States and until recently has been available at only a few academic medical centers (39).
In patients with PHEO, it is important not only to localize the primary tumor but also detect possible metastatic lesions. Detection of metastases is important for several reasons. A primary PHEO without metastases can be considered for surgical treatment. Alternatively, if metastatic PHEO is present, it is crucial to detect as many lesions as possible to optimize treatment. This is because some patients may still be candidates for surgical treatment, whereas those with more widespread disease may not.
Scintigraphy with PET is a relatively new modality using short-lived positron-emitting agents that offer the advantages of low radiation exposure, superior sensitivity, and superior spatial resolution. A variety of PET compounds other than [18F]-DA have also been used to image PHEO. [18F]-FDG has been used in one small study for imaging PHEO, showing more metastases, compared with [131I]-MIBG and [123I]-MIBG scintigraphy (16). However, all rapidly metabolizing cells take up [18F]-FDG, so PET with this agent is nonspecific and localizes a variety of tumors as well as inflammatory and infectious lesions. PET scans with [11C]-hydroxyephedrine and [11C]-epinephrine have yielded better results (17, 18), compared with [18F]-FDG, in terms of diagnostic localization of PHEO, although the short physical half-lives (T1/2 = 20 min) of these radiopharmaceuticals is an important deterrent to their more widespread use. Recently, PET with another agent, [18F]-dihydroxyphenylalanine ([18F]-DOPA), a precursor of dopamine, has been used to evaluate patients with benign PHEO (40). In this study, all 14 primary tumors were localized. Moreover, in one of three patients with extraadrenal disease, [18F]-DOPA PET was concordant with MRI results and imaged a tumor that was not seen with [131I]-MIBG. [18F]-DOPA PET has also been used for detection of carcinoids, based on the amine precursor uptake and decarboxylation pathway that characterizes these tumors (41).
Our recent experience indicates that [18F]-DA is an excellent and highly specific agent for localization of adrenal and extraadrenal PHEO, including metastatic lesions (5, 24, 25). In the present study of patients with metastatic PHEO, [18F]-DA PET scintigraphy confirmed metastatic disease in all patients and detected a much larger number of abnormal foci, compared with [131I]-MIBG scintigraphy. Because the presence of PHEO was confirmed in each patient (by elevated plasma-free metanephrines in 15 of 16 and by histopathological examination in all, we believe that these findings likely represent true positive results, although the foci imaged, for practical and ethical reasons, could not be confirmed surgically in all patients. Several advantages of [18F]-DA PET over [131I]-MIBG in the localization of PHEO should be considered. First, [18F]-DA PET results in a lower radiation dose than [131I]-MIBG scanning. [18F]-DA PET also has no particular adverse effect on the thyroid, but MIBG necessitates thyroid blocking with administration of iodine. Moreover, PET scanning can be carried out immediately after the administration of [18F]-DA, as opposed to the 24- to 48-h delay necessary for [131I]-MIBG. [18F]-DA PET also yields superior images in terms of spatial resolution, compared with the planar images obtained with [131I]-MIBG. [18F]-DA PET scanning is, however, currently available in the United States only at the NIH Clinical Center.
A limitation of this study was that the number of patients included was rather small. However, metastatic PHEO is a rare disease, and consequently only a few patients were available for study. Moreover, because of the lack of availability of [123I]-MIBG at the time of this study, we performed scintigraphy with [131I]-MIBG. Also, because only patients with confirmed metastatic PHEO were studied, only sensitivity could be calculated. Last, as a tertiary care research center, five of our 16 patients had had negative imaging work-ups before referral, including negative [131I]-MIBG scans. This likely biased our study against [131I]-MIBG scintigraphy.
In conclusion, in this study of patients with metastatic PHEO, [18F]-DA PET was superior to [131I]-MIBG scintigraphy in the localization of disease sites. Although [18F]-DA is currently available only at NIH, its synthesis/preparation is similar to that of [18F]-FDG (23), and we hope that it will become more widely available in the future.
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Footnotes |
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Received February 12, 2003.
Accepted May 18, 2003.
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