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Nuclear Medicine |
1 From the Uppsala University PET Centre, Sweden (C.T., H.E., M.B., B.L.) and Surgery Department, University Hospital, Uppsala, Sweden (C.J.). From the 2002 RSNA scientific assembly. Received December 4, 2002; revision requested February 6, 2003; final revision received July 16; accepted August 6. Address correspondence to C.T., Fundación Rioja Salud, Avenida de Portugal 7, 6°, 26001 Logroño, La Rioja, Spain (e-mail: ctrampal@frs.seris.es).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS: Nineteen patients (12 women, seven men; mean age, 53 years) suspected of having pheochromocytoma were evaluated. Patients had enlarged adrenal glands at computed tomography and either increased urinary catecholamine levels (n = 18) or normal biochemistry (n = 1). Dynamic PET examination in the adrenal region was performed after injection of 800 MBq 11C HED. PET data were analyzed visually and semiquantitatively. Time-activity curves were generated for different organs. PET results were validated with histologic evaluation (n = 16) or clinical follow-up (n = 3). The diagnostic value of HED PET was evaluated by calculating the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy.
RESULTS: In 12 patients, 13 pheochromocytomas were verified at surgery and histologic evaluation. All but one of the pheochromocytomas were detected with HED PET, which demonstrated elevated uptake. The rest of the patients (n = 7) did not have pheochromocytomas. In these patients, HED PET did not show any abnormal uptake in the suspicious tumors (confirmed at surgery in four patients and at clinical follow-up in three). Mean standardized uptake value of the tumors was 21.4 (range, 11.1–40.9). The time-activity curves for pheochromocytomas showed early uptake after injection, and the activity increased with the time of examination. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of HED PET in the detection of pheochromocytomas were 92% (12 of 13), 100% (seven of seven), 100% (12 of 12), 87.5% (seven of eight), and 95% (19 of 20), respectively.
CONCLUSION: HED PET is useful in the detection of pheochromocytomas, providing a high level of accuracy.
© RSNA, 2004
Index terms: Adrenal gland, neoplasms, 861.328 • Adrenal gland, PET, 86.12163 • Positron emission tomography (PET) • Pheochromocytoma, 861.328
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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The diagnosis of pheochromocytoma is established biochemically by measuring the level of urinary and plasma catecholamines and their metabolites. For example, a 24-hour total metanephrine and/or catecholamine test is highly sensitive (4). The primary methods of localization are anatomic imaging modalities, such as computed tomography (CT) or magnetic resonance (MR) imaging, and functional imaging techniques with metaiodobenzylguanidine (MIBG) scintigraphy. CT and MR imaging provide excellent morphologic imaging and have high sensitivities in the depiction of pheochromocytoma, but they depict only anatomic abnormalities and can fail in the discrimination between pheochromocytoma and other causes of adrenal gland enlargement (5). Scintigraphy with MIBG labeled with iodine 123 (123I) is currently the functional imaging method of choice for the localization of adrenal or extraadrenal pheochromocytomas. This imaging method provides high sensitivity and specificity but presents some disadvantages, which include limited spatial resolution and absence of sufficient uptake for visualization in some situations, such as when tumors are smaller than 1.5–2.0 cm in diameter or when large tumors have extensive necrosis and/or hemorrhage. False-negative results may occur with medications that interfere with MIBG uptake (1,6).
To solve some of these problems, another sensitive functional imaging procedure such as positron emission tomography (PET) could be of clinical utility. An imaging method using PET with carbon 11 (11C) hydroxyephedrine (HED) as a radiotracer has been developed to noninvasively obtain images of the sympathetic nervous system. Authors of previous investigations have reported substantial and selective HED uptake in organs with rich sympathetic innervation, such as the heart or adrenal medulla (7). HED PET has been used in the assessment of the sympathetic neuronal integrity of the heart (8,9) and in the characterization of pheochromocytomas, demonstrating elevated accumulation in those tumors (10). The purpose of our study was to evaluate the accuracy of HED PET in the detection of pheochromocytomas.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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Nine patients had hypertension (>140/ 90 mm Hg), and six patients presented with clinical symptoms, which consisted of headache, palpitations, and/or sweating attacks. Urinary catecholamine levels (epinephrine and norepinephrine) were increased in 18 patients; the mean epinephrine level in these patients was 421 nmol per day (range, 26–1,584 nmol/d; normal value, 0–90 nmol/d) and the mean norepinephrine level was 1,978 nmol per day (range, 49–7,608 nmol/d; normal value, 0–400 nmol/d).
The patients continued to undergo antihypertensive treatment and did not receive any medication known to interfere with HED uptake (6). An additional PET examination with 11C metomidate, which is a radiotracer developed for characterization of adrenal masses that enables identification of lesions of adrenocortical origin (11), was performed in four patients (patients 9, 12, 13, and 15).
In 16 patients, surgical therapy was performed after HED PET to obtain histopathologic confirmation. In the remaining three patients, specific follow-up was performed instead of surgery; follow-up was performed every 6 months and consisted of CT imaging and biochemical examination, which included reevaluation of urinary catecholamine levels and basal determinations of cortical adrenal function to exclude cortical hormone excess.
PET Investigation
11C HED was synthesized according to the standard good manufacturing practice, or GMP, procedures at our institution. The preparation of 11C HED has been previously described (7). PET examinations were performed by using an imager (ECAT EXACT HR Plus; Siemens/CTI, Knoxville, Tenn) that recorded 63 tomographic sections covering a transverse field of view of 155.0 mm, with a section separation of 2.46 mm and a planar resolution of 4.60 mm. Patients were placed so that the suspicious tumor was centered in the field of view, guided by CT imaging, and a short 2-minute transmission scan was obtained to locate the right diaphragmatic cupola as a reference. A 10-minute transmission scan was obtained by using a rotating external germanium 68 (68Ge) source, for attenuation correction on the subsequent emission scan. Patients received an intravenous bolus injection of a mean volume of 12 MBq 11C HED per kilogram of body weight. At the same time, a dynamic imaging sequence was started, which consisted of 14 frames (5 x 60 seconds, 5 x 180 seconds, 3 x 300 seconds, 1 x 600 seconds) and had a total examination time of 45 minutes. No blood samples were taken. The data obtained were reconstructed into transverse cross-sectional images by using filtered back projection and a 5-mm Gauss filter. From the transverse images, attenuation-corrected images were reconstructed in the coronal and sagittal planes.
The additional examination with 11C metomidate was performed by using the same model of imager. The tracer was synthesized according to the standard protocol available in our institution (11). The field of view of the PET camera was centered to include the adrenal mass, guided by a short transmission scan to identify the diaphragm. A 10-minute transmission scan was obtained by using a rotating external 68Ge source, for correction of attenuation in the emission scan. A dynamic imaging sequence was performed after intravenous injection of 10 MBq/kg 11C metomidate and consisted of 14 frames (5 x 60 seconds, 5 x 180 seconds, 3 x 300 seconds, 1 x 600 seconds) and had a total examination time of 45 minutes. No blood samples were taken. The data obtained were reconstructed into transverse cross-sectional images by using iterative reconstruction (two iterations, eight subsets) and a 5-mm Gauss filter. From the transverse images, attenuation-corrected images were reconstructed in the coronal and sagittal planes.
Data Analysis and Interpretation
Tumor uptake of HED was assessed qualitatively and quantitatively. The interpretation of PET images was made by a nuclear medicine physician (C.T.).
Qualitative analysis.—Organs with normal tracer accumulation (myocardium, liver, spleen, pancreas, normal adrenal glands in several cases, and urinary tract) were identified at visual inspection. Any increased accumulation of HED in the adrenal glands or extraadrenal regions was considered abnormal, suggesting the diagnosis of pheochromocytoma.
Quantitative analysis.—A region of interest (ROI) was placed in each of the following areas: a "hot spot" ROI (containing 3–4 pixels with the highest uptake) in the tumor, a "hot spot" ROI (if visible; containing 3–4 pixels) in the normal adrenal gland, an ROI in the liver, and an ROI in the kidney; all ROIs were placed in the transverse plane where they were clearly identifiable. The average radioactivity in these areas was calculated by using the standardized uptake value, in which we divided the radioactivity concentration in those ROIs by the ratio of the total given radioactivity and the total body weight. ROIs were copied to all frames, and time-activity curves were generated for those organs. The image evaluation and quantitation at ROI analysis were not blinded to patient data.
Both the qualitative and quantitative interpretations of 11C metomidate examinations were made by a nuclear medicine physician. Any increased tracer accumulation on the suspicious adrenal mass was considered to indicate disease and was suspicious for adrenocortical tumor. ROIs were placed on the tumors (containing 3–4 pixels with the highest uptake) and in the liver, in a plane where it was identifiable.
Statistical Analysis
The diagnostic value of HED PET was evaluated in a total of 19 patients by calculating the diagnostic sensitivity, specificity, positive predictive value, negative predictive value, and accuracy.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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Other organs that were visible within the field of view of the PET camera were the myocardium, pancreas, and spleen, but this did not interfere in the analysis and interpretation of PET data. No tracer uptake was observed in the intestinal tract.
An increase in urinary catecholamine levels was found in 11 of the 12 patients with pheochromocytoma. The only patient with pheochromocytoma and normal urinary catecholamine levels had von Hippel–Lindau disease. In this patient, routine CT evaluation depicted an adrenal mass with a diameter measuring 6 cm. Because of the possible presence of pheochromocytoma associated with that familial disease, HED PET was performed, which showed high uptake in that tumor. Further surgical examination revealed pheochromocytoma.
In regard to agreement between the 11C HED and 11C metomidate findings collected in four patients, results in patients 13 and 15 were positive at 11C HED PET, which is suggestive of pheochromocytoma, but were negative at 11C metomidate PET. Surgical examination in both patients revealed pheochromocytoma. In contrast, results in patients 9 and 12 were negative at 11C HED PET, which is not suggestive of pheochromocytoma, but were positive at 11C metomidate PET, which is consistent with adrenocortical adenoma. On the basis of these findings and those at clinical reevaluation, the diagnosis of adrenocortical adenoma was made.
The results of this HED PET investigation (12 true-positive, seven true-negative, one false-negative, and no false-positive lesions) had a sensitivity of 92% (12 of 13), a specificity of 100% (seven of seven), a positive predictive value of 100% (12 of 12), a negative predictive value of 87.5% (seven of eight), and an accuracy of 95% (19 of 20) in the detection of pheochromocytoma. When the data were analyzed on the basis of the number of patients investigated instead of the number of lesions (11 true-positive, seven true-negative, one false-negative, and no false-positive diagnoses), the sensitivity decreased slightly to 91.6% (11 of 12) and the accuracy to 94.7% (18 of 19). The specificity, positive predictive value, and negative predictive value did not change.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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PET is a functional imaging modality that noninvasively measures biochemical or physiologic processes in vivo, providing improved imaging technology that might be used as an alternative functional imaging approach to identify pheochromocytomas. The purpose of our investigation was to evaluate the role of HED PET in the detection of pheochromocytomas. HED is the first available positron-emitting tracer of the sympathetic nervous system. This agent is a catecholamine analog that accumulates in organs with sympathetic innervation, such as the heart and adrenal marrow. HED uptake reflects catecholamine transport and storage and neuronal reuptake (7,8). HED has been previously evaluated in the localization of pheochromocytomas (10) and neuroblastomas (14) and has shown elevated accumulation in both kinds of tumors. In our investigation, we found that HED PET successfully depicted pheochromocytomas by demonstrating rapid accumulation in those tumors, which were visible within a few minutes after tracer injection and showed an increase in uptake with time. All tumors detected by using HED (n = 12) were clearly differentiated from the surrounding tissue and from other organs that showed tracer uptake, such as the liver, kidney, or pancreas. Only one surgically proved pheochromocytoma, which was 3 cm in diameter, did not accumulate sufficient HED to be visible. An MIBG scintigraphy examination that was performed after the HED PET examination did not show abnormal uptake either. The patient in whom this tumor was found had hypertension and an increase in urinary catecholamine levels (both epinephrine and norepinephrine) and did not receive any medication known to interfere with catecholamine uptake (6). In addition, in all patients who did not have pheochromocytoma (n = 7), HED PET did not show any abnormal accumulation, and results were therefore not consistent with pheochromocytoma. Thus, despite the false-negative finding reported, our initial results showed that HED PET is highly sensitive (91.7%) and specific (100%) for the depiction of pheochromocytoma.
To our knowledge, only one investigation on the use of HED PET has been previously described (10). In that study, 10 patients with known pheochromocytoma were evaluated with HED PET; the tumors were detected in nine of them. The sensitivity data in that study, as well as the good PET image quality noted, are in consonance with those of our study. The results reported by these investigations show that HED PET seems to be superior to the conventional MIBG scintigraphy. In addition, HED PET may provide several potential advantages. The tomographic imaging with higher spatial resolution and the rapid and selective tracer accumulation allow the acquisition of high-quality images within a few minutes after tracer injection. In contrast, MIBG imaging may require from 24 hours to several days after tracer administration. With HED PET, since the investigation is performed in the same day, hospitalization and further inconveniences to the patient can be avoided. This PET technique allows quantification of uptake into tumors or other organs and evaluation of uptake kinetics when plotting time-activity curves for those tissues. The shorter half-life of 11C (20 minutes) allows administration of much larger doses with lower radiation exposure than can be used with MIBG, and thus it provides higher quality images (10). However, HED may present some disadvantages or limitations in relation to MIBG. HED PET is expensive, and the availability is limited. The short half-life of 11C requires on-site production of the radiotracer in a cyclotron. With this characteristic, it may be difficult to perform whole-body examinations when the intention is to identify extraadrenal tumors or metastatic disease of malignant pheochromocytomas. However, the high dose administered, which is approximately 800 MBq, and the three-dimensional image acquisitions, which may reduce the imaging time considerably, can solve this disadvantage.
Other PET radiotracers have been used to obtain images of pheochromocytoma. The most important PET radiotracer in clinical oncology is fluorine 18 (18F) fluorodeoxyglucose, which has applications in the diagnosis, staging, restaging, and therapeutic evaluation of patients with cancers of many origins (15,16). In one study, authors using fluorodeoxyglucose PET were able to localize the majority of pheochromocytomas, whether benign, malignant, intradrenal, or extraadrenal, but the specificity was low due to uptake of fluorodeoxyglucose by other neoplastic and nonneoplastic processes (17). The uptake characteristics of 18F fluorobenzylguanidine, a catecholamine analog, were experimentally investigated in dogs with spontaneous pheochromocytoma; elevated uptake was demonstrated in those tumors (18). Both 18F fluorodopamine and 18F dihydroxyphenylalanine have yielded excellent results by localizing pheochromocytomas with a high sensitivity and specificity (19,20). Both tracers are labeled with 18F, which has a longer half-life (110 minutes) than that of 11C, and they do not necessitate on-site production of the compound. Thus, these tracers may be preferable to HED for utilization in any PET center without a cyclotron, since the radiotracer can be delivered from the regional facilities.
In conclusion, results of our investigation showed that 11C HED PET is an imaging technique that provides high sensitivity and specificity in the detection of pheochromocytomas, with high-quality functional images. On the basis of these results, HED PET should be considered as the functional imaging technique of choice if the corresponding PET cyclotron facility is available.
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FOOTNOTES |
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Author contributions: Guarantors of integrity of entire study, all authors; study concepts and design, all authors; literature research, C.T., C.J., H.E.; clinical studies, C.T., C.J., H.E.; data acquisition, C.T., C.J., H.E.; data analysis/interpretation, C.T.; statistical analysis, C.T.; manuscript editing, C.T., B.L.; manuscript preparation and definition of intellectual content, revision/review, and final version approval, all authors
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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