Positron emission tomography imaging of adrenal masses: 18F-fluorodeoxyglucose and the 11ß-hydroxylase tracer 11C-metomidate
Georg Zettinig1, 2, Markus Mitterhauser1, 3, Wolfgang Wadsak1, Alexander Becherer1, 2, Christian Pirich1, 2, Heinrich Vierhapper4, Bruno Niederle5, Robert Dudczak1, 2, Kurt Kletter1
1 Department of Nuclear Medicine, University of Vienna, Vienna, Austria
2 Ludwig Boltzmann Institute for Nuclear Medicine, University of Vienna, Vienna, Austria
3 Department of Pharmaceutic Technology and Biopharmaceutics, University of Vienna, Vienna, Austria
4 Department of Internal Medicine III, University of Vienna, Vienna, Austria
5 Department of Surgery, University of Vienna, Vienna, Austria
Received: 25 January 2004 / Accepted: 13 April 2004 / Published online: 10 June 2004 @ Springer-Verlag 2004
Abstract. Purpose: 11C-metomidate (MTO), a marker of 11ß-hydroxylase, has been suggested as a novel positron emission tomography (PET) tracer for adrenocortical imaging. Up to now, experience with this very new trac- er is limited. The aims of this study were (1) to evaluate this novel tracer, (2) to point out possible advantages in comparison with 18F-fluorodeoxyglucose (FDG) and (3) to investigate in vivo the expression of 11ß-hydroxylase in patients with primary aldosteronism. Methods: Sixteen patients with adrenal masses were investigated using both MTO and FDG PET imaging. All patients except one were operated on. Five patients had non-functioning adre- nal masses, while 11 had functioning tumours (Cushing’s syndrome, n=4; Conn’s syndrome, n=5; phaeochromocy- toma, n=2). Thirteen patients had benign disease, whereas in three cases the adrenal mass was malignant (adrenocor- tical cancer, n=1; malignant phaeochromocytoma, n=1; adrenal metastasis of renal cancer, n=1). Results: MTO imaging clearly distinguished cortical from non-cortical adrenal masses (median standardised uptake values of 18.6 and 1.9, respectively, p<0.01). MTO uptake was slightly lower in patients with Cushing’s syndrome than in those with Conn’s syndrome, but the difference did not reach statistical significance. The expression of 11ß- hydroxylase was not suppressed in the contralateral gland of patients with Conn’s syndrome, whereas in Cushing’s syndrome this was clearly the case. The single patient with adrenocortical carcinoma had MTO uptake in the lower range. Conclusion: MTO could not definite-
ly distinguish between benign and malignant disease. FDG PET, however, identified clearly all three study pa- tients with malignant adrenal lesions. We conclude: (1) MTO is an excellent imaging tool to distinguish adreno- cortical and non-cortical lesions; (2) the in vivo expres- sion of 11ß-hydroxylase is lower in Cushing’s syndrome than in Conn’s syndrome, and there is no suppression of the contralateral gland in primary aldosteronism; (3) for the purpose of discriminating between benign and malig- nant lesions, FDG is the tracer of choice.
Keywords: Adrenal gland - Incidentaloma - Positron emission tomography - 11C-metomidate - FDG
Eur J Nucl Med Mol Imaging (2004) 31:1224-1230 DOI 10.1007/s00259-004-1575-0
Introduction
Incidentalomas (clinically inapparent adrenal masses) are common, and the overall frequency of adrenal adeno- mas in more than 85,000 autopsies from 25 reported studies was 5.9% (range 1-32%) [1, 2]. Since the intro- duction of computed tomography (CT) in daily routine, there has been a dramatic increase in the diagnosis of incidentalomas. Nowadays, adrenal masses are seen in approximately 2-5% of contrast-enhanced CT examina- tions, and due to the increased diagnosis of this entity, adrenal incidentalomas have become a common clinical problem [3].
The majority of adrenal incidentalomas are biochemi- cally non-functioning, but in approximately 10% of cases, an incidental adrenal mass is functional [4]. Functioning adrenocortical tumours may cause Conn’s syndrome and
e-mail: georg.zettinig@meduniwien.ac.at
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| Patient no. | Side | Diameter (cm) | Pathological classification | Clinical features | SUV max MTO lesion | SUV max MTO contralateral | SUV max MTO liver | Lesion/ contralat. ratio | Lesion/ liver ratio |
|---|---|---|---|---|---|---|---|---|---|
| 1 | Right | 3 | Benign (adrenocortical adenoma) | a | 11.5 | 5.2 | 8.7 | 2.2 | 1.3 |
| 2 | Left | 7 | Benign (adrenocortical adenoma) | a | 17.7 | 6.8 | 9.9 | 2.6 | 1.8 |
| 3 | Bilateral | 5 | Benign (macronodular hyperplasia) | a | 23.0/18.1 | n.p. | 10.2 | n.p. | 2.3/1.8 |
| 4 | Right | 1 | Benign (adrenocortical adenoma) | b | 19.1 | 15.5 | 13.9 | 1.2 | 1.4 |
| 5 | Left | 2 | Benign (adrenocortical adenoma) | b | 19.7 | 11.9 | 12.2 | 1.7 | 1.6 |
| 6 | Right | 2 | Benign (adrenocortical adenoma) | b | 15.7 | 17.1 | 8.0 | 0.9 | 2.0 |
| 7 | Left | 1.5 | Benign (adrenocortical adenoma) | b | 22.2 | 18.8 | 10.5 | 1.2 | 2.1 |
| 8 | Right | 1 | Benign (adrenocortical adenoma) | b | 21.4 | 20.2 | 9.8 | 1.1 | 2.2 |
| 9 | Right | 7 | Benign (phaeochromocytoma) | c | 1.8 | 11.1 | 10.4 | 0.2 | 0.2 |
| 10 | Left | 3 | Benign (adrenocortical adenoma) | d | 17.7 | 12.5 | 12.7 | 1.4 | 1.4 |
| 11 | Right | 4 | Benign (adrenocortical adenoma) | d | 28.6 | 22.0 | 10.2 | 1.3 | 2.8 |
| 12 | Left | 4 | Benign (adrenocortical adenoma) | d | 32.2 | 22.9 | 10.7 | 1.4 | 3.0 |
| 13 | Right | 1 | Benign (clinical follow-up) | d | 17.4 | 20.4 | 10.2 | 0.9 | 1.7 |
| 14 | Left | 10 | Malignant (adrenocortical carcinoma) | a | 14.3 | 9.2 | 9.3 | 1.6 | 1.5 |
| 15 | Right | 3 | Malignant (phaeochromocytoma) | e | 2.8 | n.p. | 8.7 | n.p. | 0.3 |
| 16 | Right | 9 | Malignant (metastasis) | f | 1.9 | n.p. | 18.1 | n.p. | 0.1 |
a Cushing’s syndrome
b Conn’s syndrome
c Phaeochromocytoma
d Hormonally inactive adenoma
e Phaeochromocytoma, history of left-sided adrenalectomy
Cushing’s syndrome, and phaeochromocytomas may cause excess release of adrenaline and noradrenaline. Functioning adrenal tumours require surgical treatment. The evaluation and treatment of non-functional adrenal tu- mours, however, is still a matter of discussion. CT and magnetic resonance imaging (MRI) are the routine imag- ing methods for the preoperative evaluation of adrenal masses, but positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) is also increasingly used for this purpose. Recently, 11C-metomidate (MTO) was introduced as a novel PET tracer for adrenocortical imag- ing. This substance is an inhibitor of 11ß-hydroxylase (CYP11B1, P450118), an enzyme essential in the biosyn- thesis of aldosterone and cortisol. It catalyses the 11ß-hy- droxylation of 11-deoxycortisol to cortisol and of 11-de- oxycorticosterone to corticosterone and is regulated by adrenocorticotropin [5, 6]. Imaging of adrenocortical tumours with this tracer has been previously described by Bergström et al. [7]. These authors reported that MTO is attractive for the characterisation of adrenal masses as it possesses the ability to discriminate lesions of adrenocor- tical origin from non-cortical lesions and that it may also be of use for the discrimination of benign from malignant lesions [7]. To date, however, MTO has been evaluated only by this one group. Recently, we started to evaluate the production of this tracer at our department [8, 9].
The aims of this study were (1) to evaluate this novel tracer, (2) to point out possible advantages in comparison with FDG and (3) to investigate in vivo the expression of 11ß-hydroxylase in patients with primary aldosteronism.
f Metastasis of a clear cell renal cancer, history of left-sided adren- alectomy and nephrectomy n.p., Determination not possible (patient no. 3, bilateral disease; patient nos. 15 and 16, history of contralateral adrenalectomy)
Materials and methods
Patients
Sixteen patients with adrenal masses were investigated using both FDG and MTO PET imaging (median age 56 years, range 29-72 years, four females). Five patients had non-functioning adrenal masses, while 11 had functioning tumours (Cushing’s syndrome, n=4; Conn’s syndrome, n=5; phaeochromocytoma, n=2). Thirteen patients had benign disease, whereas in three individuals, the adre- nal mass was malignant. The clinical and pathological features of all study participants are detailed in Table 1. None of the patients was treated with chemotherapy or was receiving any medication known to interfere with 11ß-hydroxylase activity.
All study patients underwent MTO and FDG PET imaging on a dedicated full ring PET scanner (Advance, General Electric Medical Systems, Milwaukee, WI). In 13 patients the two PET scans were performed within 2 days, while in the other three pa- tients the interval between MTO and FDG imaging was 3, 10 and 29 days, respectively. Fifteen patients had surgery with detailed histological examination of the tumours. A single patient refused surgery and was followed up over 2 years clinically and radiologi- cally. MTO PET imaging was approved by the Ethical Committee of the University of Vienna, and the study participants gave their written informed consent to participation.
Synthesis of MTO
MTO was synthesised as previously reported by reacting (R)-1-(1- phenylethyl)-1H-imidazole-5-carboxylic acid with 11C-methylio- dide [9]. MTO was prepared in activities up to 11 GBq starting from ~60 GBq 11C-CO2. Average radiochemical purity was
>99% and specific radioactivity was up to 63.3 GBq/umol, aver- aging 14.4 GBq/umol; the activity concentration was up to 1,048 MBq/ml.
MTO PET imaging
MTO imaging was performed in all patients following the same protocol after overnight fasting. A 10-min transmission scan was performed for attenuation correction of subsequent emission scans, and thereafter a median activity of 820 MBq MTO was ad- ministered intravenously (range 425-1,100 MBq). All patients were injected at the PET scanner. Dynamic images were acquired in two-dimensional standard mode with a matrix size of 128x128 according to a previously published protocol; acquisition was per- formed in 14 frames over 45 min (frames 1-5, 60 s; frames 6-10, 180 s; frames 11-13, 300 s; frame 14, 600 s). Frames 9-14 (15-45 min after injection) were summed. The images were recon- structed using an iterative algorithm and a 6-mm Hanning filter. In addition to visual interpretation of both the dynamic and the summed images and comparison with the morphological imaging methods, semiquantitative analysis was performed. Standardised uptake values (SUVs) were calculated by drawing regions of inter- est over the adrenal mass and the normal adrenal gland. In addi- tion, a hot spot in the liver was used as a reference region. Maxi- mal SUVs of each region of interest are given.
FDG PET imaging
The study participants received a median activity of 367 MBq 18F-FDG followed by 20 mg furosemide intravenously after at least 6 h of fasting. At the time of tracer administration, all pa- tients had glucose levels within the normal range. Forty minutes after injection, an emission scan from the upper legs to the head was performed. All patients underwent the same protocol. Scan time was 5 min per step, and acquisition was performed in two- dimensional standard mode with a matrix size of 128x128. Images were reconstructed using an iterative EM algorithm. In addition to visual assessment, SUVs were calculated for both adrenal glands.
Statistics
Results are given as median (range). The Mann-Whitney U test was used for non-parametric comparison of groups, and a p value <0.05 was considered significant. “Median SUV” stands for the median of the maximal SUVs of particular regions of interest.
Results
General imaging features of MTO
The MTO PET studies of showed a tissue distribution similar to that reported by Bergström et al. [10]. Within the first minute, a distribution pattern analogous to a per- fusion study was found; aorta, large blood vessels and kidneys were clearly seen. Thereafter, the tracer accumu- lated in the liver, the stomach and the adrenal glands. The peak of radioactivity in the stomach was seen 15-20 min
a
b
after injection, followed by a clear washout period of gas- tric activity. In the liver, peak activity was reached ap- proximately 5 min after tracer administration, followed by a slight decrease in most cases. A few minutes after injection, the adrenal glands were clearly visible in all patients, and accumulation of MTO occurred until the acquisition was terminated. The liver had a median SUV of 10.2 (range 8.0-18.1), and the median SUV of the ad- renal glands was 17.7 (range 5.2-32.2). All adrenal glands could be easily delineated visually. Table 1 details the semiquantitative analysis, and in Figs. 1, 2 and 3 the scintigraphic findings of illustrative patients are shown.
Assessment of cortical versus non-cortical lesions with MTO
Cortical lesions had a median SUV of 18.6 (range 11.5-32.2), whereas the SUVs of the three patients with non-cortical lesions were 1.8, 1.9 and 2.8, respectively. The difference in SUV between cortical and non-cortical lesions was statistically significant (p<0.01).
a
=
S
b
1
Assessment of Cushing’s syndrome versus Conn’s syndrome with MTO
MTO uptake in the hyperfunctioning glands of the pa- tients with Conn’s syndrome was slightly higher than that in patients with Cushing’s syndrome. However, this difference was not statistically significant: the median SUV in the four patients with Cushing’s syndrome was 17.7 (range 11.5-23.0), while that in the five patients with Conn’s syndrome was 19.7 (range 15.7-22.0).
Among the patients with a preoperative diagnosis of Cushing’s syndrome, two had unilateral benign adreno- cortical tumours, one had bilateral adrenocortical tu- mours and another had an adrenocortical carcinoma. In the two patients with unilateral, benign Cushing’s syndrome, the hyperfunctioning gland markedly sup- pressed the contralateral one; thus the ratio of the maxi- mal SUV of the hyperfunctioning gland to that of the normal gland was 2.2 and 2.6, respectively. In the single patient with adrenocortical cancer, a similar result was obtained (corresponding ratio of 1.6). In the patients with Conn’s syndrome no such observation was made, the median ratio of the maximal SUV of the hyperfunc-
a
>
b
tioning gland to that of the normal gland being 1.2 (range 0.9-1.7).
Evaluation of malignant status with MTO
This series included only a single patient with adreno- cortical carcinoma, and MTO PET could not identify this malignancy. This patient with adrenocortical cancer had an SUV of 14.3, which was within the lower range of patients with benign adrenocortical masses.
FDG PET imaging
FDG PET clearly distinguished all malignant lesions from the benign adrenal masses. The three malignant lesions had a median SUV of 6.6 (range 5.6-8.8), whereas in benign lesions a median SUV of 2.2 (range 1.2-3.9) was seen. This difference was statistically significant (p=0.005). FDG PET imaging showed a specificity, sensitivity and diagnostic accuracy of 100% for characterisation of the status (malignant vs benign) of adrenal lesions.
Discussion
This is the first study to confirm the findings published by the Swedish group who introduced MTO PET imag- ing. We observed a similar tracer distribution and similar imaging characteristics to those described by Bergström et al. [10]. MTO is a potent tracer for the discrimination of adrenocortical lesions. Previous studies by Bergström et al. [7] using frozen section autoradiography showed that 11C-MTO, an imidazole-based methyl ester and a potent inhibitor of 11ß-hydroxylase, had very high up- take in the adrenal cortex and adrenal cortical tumours but low uptake in the other examined organs, with the exception of the liver. This finding could have been due to the hepatic cytochrome P450 enzyme system, for which MTO may be presumed to have a slight affinity. In a subsequent study, the same group investigated MTO PET imaging in 15 patients with adrenal lesions. They found very high uptake in normal adrenals and adrenal adenomas as well as in adrenocortical cancer, whereas all lesions of non-adrenal origin had such low uptake that they could not be discriminated from surrounding tissues. Our data confirm that MTO is an excellent tracer for the discrimination of adrenocortical from non-corti- cal lesions, and whenever this question is clinically rele- vant, MTO PET imaging is a valuable tool. However, for valid interpretation, functional PET imaging needs to be correlated with morphological imaging methods such as CT or MRI to guarantee information about the exact localisation of the lesion. Tracer uptake in the adrenal lesions varied, and in contrast to the Swedish group, we could not find a relation between MTO uptake and cer- tain adrenocortical pathologies. Bergström et al. reported that their two patients with adrenocortical cancer had lower uptake than their patients with adrenocortical ade- nomas. Our single patient with adrenocortical carcinoma also had an SUV in the lower range. MTO PET imaging features, however, did not differ significantly from those in patients with benign disease. FDG PET imaging, by contrast, clearly identified malignancy not only in the case of the aforementioned adrenocortical carcinoma but also in the other two malignant adrenal lesions.
Because of the high specificity of MTO for adreno- cortical tissue, this tracer may be of promise for staging of patients with adrenocortical cancer. Recently, a de- tailed evaluation of MTO PET imaging in adrenocorti- cal cancer was published by Khan et al. [11]. The authors reported that adrenocortical cancer was clearly visualised with MTO. We also investigated two pilot pa- tients with adrenocortical cancer in whom MTO PET had superior imaging features compared with FDG PET imaging [12]. For these patients, MTO might be the ideal tracer, although we have previously demonstrated that FDG is a potent tracer even for adrenocortical can- cer patients [13]. As MTO might be superior to FDG in patients with adrenocortical cancer, we have recently evaluated an 18F-labelled tracer (2-[18F] fluoroethyl-
desethyl-(R)-etomidate, FETO) suitable for whole-body imaging [14].
Nuclear imaging of adrenal masses may also be per- formed with 131I-iodomethylnorcholesterol and 75Se- selenocholesterol. These tracers have also been reported to distinguish non-functioning, benign adrenal lesions from other space-occupying ones with high sensitivity, specificity, accuracy and cost-effectiveness [15, 16]. For the imaging of non-glucocorticoid-secreting adrenal lesions (primary aldosteronism and adrenal hyperandro- genism), dexamethasone suppression is routinely per- formed, as suppression of the inner zones of the cortex has been shown to improve diagnostic performance. After comparison with morphology, the differential diag- nosis of cortical versus non-cortical lesions is easy. A feasible approach for the characterisation of hyperfunc- tioning glands in particular patients with primary aldos- teronism might be performance of MTO PET imaging after dexamethasone suppression: In our two patients with benign unilateral Cushing’s syndrome, the hyper- functioning adrenal gland clearly suppressed the contra- lateral one, as is also seen in other endocrinological dis- orders [17]. We could not verify this observation in the five patients with Conn’s syndrome, as only a single pa- tient with Conn’s syndrome showed a marked difference between the glands. These findings indicate that dexa- methasone suppression might be helpful when MTO PET imaging is performed to evaluate patients with non- glucocorticoid-secreting adrenocortical lesions.
As it is well known that the differentiation between functioning and non-functioning adrenocortical lesions can be made with high diagnostic accuracy and cost- effectiveness using 131I-iodomethylnorcholesterol, it re- mains somewhat unclear whether use of 11C-metomidate would be advantageous. Due to the limited availability of 11C-labelled tracers, 11C-metomidate will certainly not play a role in clinical routine, but it does provide in- sights into the endocrine situation in adrenal hyperfunc- tional disorders. Possibly an 18F-labelled tracer such as FETO [14] will replace 131I-iodomethylnorcholesterol imaging in the future.
As yet, only limited data have been reported on FDG PET imaging of adrenal masses. Yun et al. reported a large study on 50 adrenal lesions in 41 patients [18]. In their study, FDG PET showed a sensitivity of 100%, a specificity of 94% and an accuracy of 96%. Prior to this study, only a few case reports, a small patient series, and an analysis of patients with adrenal masses and a history of bronchogenic carcinomas had been reported [19-21]. Our analysis of FDG PET imaging in a larger patient sample with adrenal adenomas also demonstrates excel- lent imaging features for the discrimination between benign and malignant adrenal masses.
The presence and pathophysiological role of 11ß- hydroxylase in the zona glomerulosa of patients with Conn’s syndrome is still a matter of controversy. In vitro studies with conventional reverse transcription-polymer-
ase chain reaction (RT-PCR), [22, 23] real time RT-PCR [24] and in situ hybridisation [25, 26] have shown the presence of 11ß-hydroxylase in human aldosterone- producing adenomas, which are commonly believed to originate from glomerulosa cells, while other studies have not demonstrated this [27]. This is the first in vivo study to investigate 11ß-hydroxylase expression in pa- tients with Conn’s syndrome, and our findings also suggest increased expression of this enzyme. However, there was no suppression of the contralateral gland in primary aldosteronism.
Conclusion
Summarising our findings, MTO is an excellent imaging tool for distinguishing adrenocortical from non-cortical lesions. For discrimination between benign and malig- nant lesions, FDG is the tracer of choice. The in vivo expression of 11ß-hydroxylase was lower in the patients with Cushing’s syndrome than in those with Conn’s syn- drome, and there was no suppression of the contralateral gland in primary aldosteronism.
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