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1 From the Divisions of Nuclear Medicine (S.H., E.N., I.B., E.M.) and Diagnostic Radiology (C.A., N.G.), Department of Radiology; and Divisions of Nephrology and Hypertension (T.M., H.P.H.N.) and Endocrinology (M.R.), Department of Internal Medicine, Albert-Ludwigs University, Hugstetter Strasse 55, 79106 Freiburg, Germany. Received March 16, 2001; revision requested April 18; revision received July 17; accepted August 9.
| ABSTRACT |
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MATERIALS AND METHODS: 18F DOPA PET and magnetic resonance (MR) imaging were performed in 14 consecutive patients suspected of having pheochromocytomas (five sporadic, nine with von Hippel-Lindau disease); metaiodobenzylguanidine (MIBG) scintigraphy was performed in 12 of these patients. The individual imaging findings were assessed in consensus by specialists in nuclear medicine and radiologists blinded to the results of the other methods. The findings of the functional imaging methods were compared with those of MR imaging, the reference standard. Histologic verification could be obtained in eight patients with nine tumors.
RESULTS: Seventeen pheochromocytomas (11 solitary, three bifocal; 14 adrenal, three extraadrenal) were detected with MR imaging. 18F DOPA PET and MR imaging had concordant results in all 17 tumors. In contrast, MIBG scintigraphy had false-negative results in four patients with three adrenal tumors smaller than 2 cm and one extraadrenal tumor with a diameter of 3.6 cm. On the basis of these data, sensitivities of 100% for 18F DOPA PET and of 71% for MIBG scintigraphy were calculated. Specificity was 100% for both procedures.
CONCLUSION: 18F DOPA PET is highly sensitive and specific for detection of pheochromocytomas and has potential as the functional imaging method of the future.
Index terms: Adrenal gland, MR, 86.121411, 86.121412, 86.121416 • Adrenal gland, neoplasms, 861.328 • Adrenal gland, PET, 86.12163 • Adrenal gland, SPECT, 86.12161, 86.12162, 86.12172, 86.12175 • Fluorine, radioactive • Pheochromocytoma, 861.328
| INTRODUCTION |
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Although biochemical examinations, such as urinary catecholamine tests, alone are highly sensitive for pheochromocytoma detection (2), diagnostic imaging is important for localizing the tumor and helping to exclude multifocal tumor lesions before surgical resection (3,4). To our knowledge, thus far there is no standardized imaging protocol, and a multitude of imaging modalities have been performed frequently, especially in patients with hereditary tumors. In addition to morphologic tomographic imaging modalities such as computed tomography (CT) and magnetic resonance (MR) imaging, functional imaging methods such as metaiodobenzylguanidine (MIBG) scintigraphy and indium 111 pentetreotide scintigraphy have been used in the detection of pheochromocytomas (2,5–8).
For many years MIBG scintigraphy has been the functional imaging method of choice to help obtain specific proof of tumor and to assess tumor spread (7). The disadvantages of this procedure are limited spatial resolution and a lack of tracer uptake in some tumors, both of which lead to false-negative results. Therefore, a highly sensitive and specific functional imaging procedure would be of great clinical utility. Positron emission tomography (PET) with use of the radiopharmaceutical agent fluorine 18 (18F) dihydroxyphenylalanine (DOPA) has the potential to fulfill these requirements. This examination is based on the capability of neuroendocrine tumors to take up, decarboxylate, and store amino acids, such as DOPA, and their biogenic amines (9,10). The purpose of the present study was to evaluate 18F DOPA whole-body PET as a biochemical imaging examination for the diagnosis of pheochromocytomas.
| MATERIALS AND METHODS |
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For inclusion in the study, each patient had to fulfill at least one of the following criteria: typical clinical symptoms of pheochromocytoma, hypertension, and/or elevated urinary catecholamine levels. Three patients presented with only the classic triad of headache, palpitation, and sweating attacks, whereas their blood pressure and urinary catecholamine levels were in the upper range of normal. Blood pressure measurements indicated hypertension (>140/90 mm Hg) in seven patients, and urinary catecholamine levels were increased (mean epinephrine level ± SD, 17 µg/24 h [92.8 nmol/d] ± 28 [normal level, 2–20 µg/24 h, or 10.9–109.2 nmol/d]; mean norepinephrine level, 249 µg/24 h [1,471.6 nmol/d] ± 247 [normal level, 20–80 µg/24 h, or 118.2–472.8 nmol/d]) in 10 patients.
Five patients had sporadic pheochromocytomas, and nine had von Hippel-Lindau disease. The high percentage of hereditary diseases resulted from the fact that the patient population was largely derived from patients treated at a center for hereditary pheochromocytomas. All tumors were classified as benign. In eight patients, surgical therapy was performed after imaging; the remaining six patients rejected surgery for the time being.
18F DOPA PET
All patients fasted for at least 6 hours prior to the 18F DOPA PET examination to achieve optimal conditions for uptake of the radiopharmaceutical agent. 18F DOPA was produced by using a standard procedure (11). A mean volume of 220 MBq ± 35 (SD) of 18F DOPA was injected intravenously; the uptake time was 90 minutes. Emission and transmission data were acquired by using a two-dimensional ring scanner (Ecat Exact; Siemens/CTI, Knoxville, Tenn). Eight to 10 bed positions with an 11-cm axial field of view were measured (2 minutes for transmission, 8 minutes of emission per position). Image reconstruction was performed by using an iterative procedure with ordered subsets (ordered subset-expectation maximization, two iterations, eight subsets) and postinjection segmented attenuation correction (12). No pre- or postfiltering was used, and the final reconstruction resolution of the images was 6 mm (12).
Comparison of Patient and Control Group Findings
The patient findings were compared with those obtained in a control group to determine the normal distribution of 18F DOPA in the body. The control group consisted of eight consecutive patients in whom an 18F DOPA examination was clinically indicated for assessment of possible Parkinson disease. None of these patients had neuroendocrine or other types of tumors.
MIBG Scintigraphy
No patient received any drugs that would interfere with MIBG uptake, such as tricyclic antidepressants, reserpine, or sympathomimetic amines. Following the intravenous injection of a mean of 170 MBq ± 20 of iodine 123 (123I) MIBG (Nycomed Amersham, Amersham, England), planar scintigraphic images were obtained with a large field of view gamma camera (Bodyscan; Siemens, Erlangen, Germany) and a low-energy collimator. Twenty-four and 48 hours after injection, whole-body images in the ventral and dorsal planes, as well as target images of the abdomen and thorax, were acquired. Single photon emission CT (SPECT) of the thorax and abdomen was performed 24 hours after injection by using a triple-headed camera (Prism XP 3000; Picker Marconi, Cleveland, Ohio) and the following parameters: a 128 x 128 matrix, 120 projections in 3° angle increments, and an acquisition time of 40 seconds per projection. Image reconstruction was performed by using filtered back projection, with no prefiltering, reconstruction with a ramp filter, and postprocessing with a low-pass filter.
Interpretation of PET and MIBG Scintigraphic Studies
Two of the authors (S.H., E.N.), nuclear medicine specialists, assessed the reconstructed 18F DOPA PET and MIBG SPECT scans on a computer monitor in all three planes—transverse, coronal, and sagittal—by using an inverse gray scale. In addition to the MIBG SPECT scans, all planar MIBG images, which were obtained 24 and 48 hours after injection, were included for assessment of MIBG scintigraphy. The 18F DOPA PET and MIBG scans obtained in each patient were interpreted at different times, with blinding to the clinical data and the results of the other studies. The two authors interpreted these images in consensus; there were no disagreements.
Any focal accumulation of 18F DOPA or MIBG in the adrenal glands or extraadrenal regions that exceeded the normal regional tracer uptake volume was considered a pathologic finding—that is, pheochromocytoma. 18F DOPA PET tracer uptake was classified in two categories: Massive tracer uptake was defined as an accumulation that was comparable to that in the renal collecting system, and moderate uptake was defined as an accumulation that was distinctly weaker than that in the renal collecting system but still showed clear contrast relative to the surrounding tissue. MIBG uptake was classified as follows: High tracer uptake was defined as an accumulation that could be clearly identified on planar images alone, whereas moderate uptake was hardly visible on the planar images but could be seen on the SPECT images due to the better contrast. Another essential criterion for the diagnosis of adrenal pheochromocytomas at MIBG scintigraphy was side asymmetry of the adrenal glands. Linear, nonfocal limited intestinal uptake was considered a nonspecific, nonpathologic finding at 18F DOPA PET and MIBG scintigraphy.
MR Imaging
MR imaging was performed with a 1.5-T unit (Magnetom Vision or Symphony; Siemens) by using a surface, or body-array, coil. In all patients, transverse and coronal images were acquired during a single breath hold. The standard dose of 0.1 mmol/kg of gadopentetate dimeglumine (Magnevist; Schering, Berlin, Germany) was injected. The following sequences were performed with the Vision imaging unit: nonenhanced transverse and coronal T2-weighted turbo spin-echo (5,130–5,328/120 [repetition time msec/echo time msec]) and T1-weighted fast low-angle shot gradient-echo (141–144/4, 70° flip angle) imaging performed before and after contrast medium administration. The following sequences were performed with the Symphony imaging unit: nonenhanced transverse and coronal T2-weighted turbo spin-echo (2,310–2,872/120) and T1-weighted fast low-angle shot gradient-echo (123–148/4.8, 70° flip angle) imaging performed before and after contrast medium administration. Spectral fat saturation was applied at all contrast material–enhanced T1-weighted imaging examinations. The section thickness was 5–6 mm in all cases.
Interpretation of MR Images
Two authors (C.A., N.G.) blinded to the clinical data and the scintigraphic and PET results interpreted the MR images on a computer monitor. They interpreted the images in consensus, and there were no disagreements. According to known MR characteristics, every adrenal and extraadrenal soft-tissue mass with high signal intensity on T2-weighted MR images—as compared with the signal intensity of liver and muscle—that showed strong enhancement after contrast medium administration was classified as a pheochromocytoma (13,14). In addition to localization and contrast enhancement, the size, margins (ie, well-circumscribed vs infiltrative growth pattern), and structure (ie, calcifications or necrosis) of the tumors were evaluated.
Reference Standard
Because histologic verification, which would have been the only real reference standard, could be obtained in only eight of the 14 patients, MR imaging was used as the reference standard for comparison with the functional imaging procedures—that is, 18F DOPA PET and MIBG scintigraphy. MR imaging is known to be highly sensitive in the detection of pheochromocytomas (2,5), and there were no discrepancies between the MR imaging results and the histologic findings obtained in the eight patients. The sensitivity and specificity of the functional procedures were calculated from these data. 18F DOPA PET specificity was evaluated on the basis of findings in the 14 adrenal glands without tumors and in the 11 extraadrenal regions in the patients without extraadrenal tumors (n = 25). MIBG scintigraphy specificity was calculated on the basis of findings in the 12 normal adrenal glands and in the 10 tumor-free extraadrenal regions (n = 22) examined by using MIBG scintigraphy.
| RESULTS |
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MIBG scintigraphy was performed in 12 patients (two patients rejected MIBG scintigraphy), and it depicted 10 tumors in nine of these patients. Eight tumors had high tracer uptake, and two had moderate uptake. All normal adrenal glands could be identified by using the SPECT technique.
Compared with MR imaging and PET, both of which depicted a total of 14 tumors in these 12 patients, MIBG scintigraphy was false-negative in four of these 14 pheochromocytomas. Three of these false-negative tumors were smaller than 2 cm in diameter. One of these three tumors was observed in a patient with bilateral tumors in whom the larger neoplasm (diameter, 3.8 cm) was detected by using MIBG scintigraphy. The fourth false-negative finding was an extraadrenal tumor that did not show any MIBG uptake, despite having a diameter of 3.6 cm (Fig 2). The false-negative results in two patients were histologically verified; the other two patients had von Hippel-Lindau disease and concordant MR imaging and 18F DOPA PET results that unequivocally indicated pheochromocytoma. The sensitivity of MIBG scintigraphy was calculated to be 71% (10 of 14 tumors); and the specificity, 100% (22 of 22 tumor-free adrenal and extraadrenal regions).
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| DISCUSSION |
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Thus far, there has been little experience with PET imaging of pheochromocytomas. PET approaches with 2-[fluorine-18]fluoro-2-deoxy-D-glucose, or FDG, the standard PET radiopharmaceutical agent in oncology, and with carbon 11 (11C) hydroxyephedrine, a catecholamine analog, have been described (15,16). While FDG uptake in pheochromocytomas has been shown to be limited and frequently worse than MIBG uptake, hydroxyephedrine PET has yielded good results (15,16). Despite its good image quality, however, this technique has not had general acceptance and use, because the short half-life of the 11C isotope hardly allows whole-body examinations and necessitates on-site production of the radiopharmaceutical agent. These disadvantages can be completely avoided by using the 18F DOPA PET technique described herein. This examination can be performed easily with any PET scanner.
18F DOPA PET has thus far been used nearly exclusively for brain examinations (17,18), and only a few reports in the literature (19–21) show the value of whole-body examinations for diagnostic imaging of neuroendocrine gastrointestinal tumors and medullary thyroid carcinoma. To our knowledge, the detection of pheochromocytomas with 18F DOPA PET had not been described in the literature before now. Because these tumors also manifest in the neuroendocrine system and virtually all of them show dopamine synthesis by means of DOPA decarboxylation, the theoretical prerequisites for the detection of pheochromocytomas are much better than those for the detection of the majority of the other neuroendocrine tumors.
Compared with MIBG scintigraphy, 18F DOPA PET has several advantages: Thanks to the favorable physical conditions of positron emitters, PET enables higher spatial resolution than do conventional nuclear medicine imaging techniques. This higher spatial resolution, in combination with the observed selective and distinct tracer accumulation, enables the acquisition of excellent-quality images within 4 hours, whereas the acquisition of MIBG scintigrams can be performed 24 hours after contrast medium injection at the earliest. The good image quality of 18F DOPA PET enables the detection of even small lesions. A special advantage of 18F DOPA PET is the lack of uptake in normal adrenal glands; this was observed not only in the current study but also in studies involving a multitude of patients suspected of having medullary thyroid carcinomas and gastrointestinal carcinoid tumors (20,21). Thus, it must be assumed that every uptake at this site at 18F DOPA PET should be classified as a pathologic finding.
In contrast, some degree of MIBG uptake is normally seen in healthy adrenal glands. This physiologic uptake in normal adrenal glands is especially imaged with the overlapping free SPECT technique. Therefore, the most important diagnostic criterion at MIBG scintigraphy is the side asymmetry. This criterion of side asymmetry can lead to misinterpretations, particularly in bilateral processes. Furthermore, MIBG scintigraphy can fail to depict small lesions, and even large tumors can lack MIBG uptake, although they will show massive 18F DOPA accumulation. These facts indicate that 18F DOPA PET may be more sensitive than MIBG scintigraphy, which has reported sensitivities of 79%–95% and a reported cumulative sensitivity of 88% (2,7,8). One of these reports (8) also demonstrates that 123I MIBG, which was used in this study, yields better image quality and higher sensitivity than does iodine 131 MIBG.
18F DOPA PET yields the same sensitivity as MR imaging, which is known to have very high sensitivity (2,5). Moreover, functional imaging may offer several advantages over morphologic imaging. One of these advantages is that one session of whole-body imaging can enable the important exclusion of multifocal or metastasizing pheochromocytomas, which occur particularly in patients with hereditary tumors. Furthermore, functional imaging with 18F DOPA PET enables the metabolic assessment of small structures (eg, lymph nodes in metastasizing tumors), which cannot be unequivocally assessed by using morphologic imaging alone, and the differentiation between scars and tumor recurrence after previous surgery (19–21). Although the results of this study do not show these advantages specifically for pheochromocytomas, the proof of these findings has already been rendered for other neuroendocrine tumors that are associated with even worse prerequisites for 18F DOPA PET imaging (19–21).
Another advantage is the extremely high specificity of functional imaging; the specificity of MIBG scintigraphy reported in the literature is 95%–99% (2,7). As our study data show, the specificity of 18F DOPA PET seems to be similar to that of MIBG scintigraphy. This can be explained by the fact that only the cells of the amine precursor uptake and decarboxylation system are able to take up, decarboxylate, and store amino acids and their amines (20,21).
It has been shown that the combined application of morphologic tomographic imaging for assessment of the shape and structure and PET for assessment of metabolism can yield excellent diagnostic results in the setting of neuroendocrine gastrointestinal tumors (19,20). The same should apply particularly to patients suspected of having multiple or malignant pheochromocytomas.
A limitation of the present study is the small number of patients, which was due to the rarity of the disease. Moreover, not all lesions could be verified histologically since six patients rejected surgical therapy because they had no or mild hypertension and either no or only moderate clinical symptoms. This wait-and-see strategy may be justified, especially for patients with von Hippel-Lindau disease, since new pheochromocytomas at other locations can occur anytime. Due to this lack of histologic verification, all of the sensitivities and specificities reported in this study are relative to MR imaging. This is an important limitation, although a high sensitivity and specificity of MR imaging must be assumed due to literature data that indicate a sensitivity of 95% (2), the agreement with histologic findings in this study, and the fact that we observed no lesions that were detected only by using the functional imaging methods. Although such lesions would have had to be classified as false-positive MIBG and 18F DOPA findings in the study design that we used, the absence of such discrepancies confirms the high sensitivity of MR imaging and precludes, at least for this patient population, a higher sensitivity of the functional imaging procedures.
Furthermore, every lesion diagnosed by using MR imaging showed MIBG and/or 18F DOPA uptake, which indicates the high specificity of MR imaging. Despite the high sensitivity and specificity of MR imaging, however, functional imaging with 18F DOPA PET might be superior in some patients—namely, those with multiple and malignant metastasizing extraadrenal tumors and those with adrenal pheochromocytomas that do not have the typical MR imaging characteristics—because of the reasons just discussed. Further studies are needed to evaluate this hypothesis.
In conclusion, our initial study results show that 18F DOPA PET seems to be a highly sensitive and specific biochemical imaging approach for detection of pheochromocytomas. Therefore, it has the potential to be the functional imaging method of the future, after the results reported herein are confirmed in a larger patient population.
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