Contemporary adrenal scintigraphy

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Eur J Nucl Med Mol Imaging (2007) 34:547–557 DOI 10.1007/s00259-006-0265-5

OCCASIONAL SURVEY

Contemporary adrenal scintigraphy Milton D. Gross & Anca Avram & Lorraine M. Fig & Domenico Rubello

Received: 15 June 2006 / Accepted: 8 August 2006 / Published online: 25 November 2006 # Springer-Verlag 2006

Abstract Introduction High-resolution computed tomography (CT) and magnetic resonance (MR) imaging have replaced scintigraphy as primary imaging modalities for the evaluation of adrenal diseases. Discussion Thin-slice CT, CT contrast washout studies and MR pulse sequences specifically designed to identify adrenal lipid content have radically changed the approach to anatomic imaging and provide unique insight into the physical characteristics of the adrenals. With a confirmed biochemical diagnosis, further evaluation is often unnecessary, especially in diagnostic localization of diseases of the adrenal cortex. However, despite the exquisite detail afforded by anatomy-based imaging, there are not infrequently clinical situations in which the functional insight provided by scintigraphy is crucial to identify adrenal dysfunction and to assist in localization of adrenocortical and adrenomedullary disease. The introduction of hybrid PET/CT and SPECT/CT, modalities that directly integrate anatomic and functional information, redefine the radiotracer principle in the larger context of high-resolution M. D. Gross : A. Avram : L. M. Fig Department of Radiology, Division of Nuclear Medicine, University of Michigan, Ann Arbor, MI, USA M. D. Gross (*) : L. M. Fig Nuclear Medicine Service (115), Department of Veterans Affairs Health System, 2215 Fuller Rd, Ann Arbor, MI 48105, USA e-mail: [email protected] D. Rubello Nuclear Medicine Service-PET Unit, S. Maria della Misericordia Rovigo Hospital, Istituto Oncologico Veneto (IOV), Rovigo, Italy

anatomic imaging. Instead of becoming obsolete, scintigraphy is an element of a device that combines it with CT or MR to allow a direct correlation between function and anatomy, whereby the combination creates a more powerful diagnostic tool than the separate component modalities. Keywords Scintigraphy . Adrenal . Adrenocortical . Adrenomedullary . Radiopharmaceutical

Introduction Contemporary adrenal imaging relies heavily upon computed tomography (CT) as the primary modality of adrenal localization. The availability of CT in clinical practice makes it ideal for evaluating adrenal gland morphology [1]. Magnetic resonance (MR) also provides high-resolution imaging and tissue characterization [1]. It, too, has been used to diagnostic advantage in the evaluation of the adrenal cortex and medulla. Other modalities, such as adrenal vein hormone sampling, have value in selected cases in which neither anatomic nor functional imaging can discern the site(s) of adrenal hormonal hypersecretion. However, even with the availability of high-resolution imaging techniques, adrenal scintigraphy continues to provide useful information in depicting and staging neoplasms and differential function of the adrenals (Table 1) [2]. Scintigraphic studies of the adrenal glands take advantage of radiopharmaceuticals with specific affinity for unique functional characteristics of the adrenal cortex and adrenal medulla [3–5]. Radiopharmaceuticals designed for adrenal imaging enter hormone biosynthetic pathways as precursors, as compounds that mimic hormones or as ligands that possess affinity for specific tissue receptors. Taking advantage of these unique endocrine tissue charac-

548 Table 1 Clinical utility of adrenal scintigraphy

Modified and used with permission from [2]: Gross MD, Rubello D, Shapiro B. Is there a future for adrenal scintigraphy? Nucl Med Commun 2002;23:197–202 131 NP-59 I-6β-iodomethyl75 norcholesterol, SMC Seselenomethyl-norcholesterol, 18 FDG F-fluorodeoxyglucose, 11 MTO C-metomidate, 131 123 MIBG I ( I)metaiodobenzylguanidine, 123 111 In-octreotide OCT I, 11 and analogs, EPI C-epineph11 rine, HED C-hydroxyephe18 drine, DA 18 F-dopamine, DOPA F-dihydroxyphenylalanine

Eur J Nucl Med Mol Imaging (2007) 34:547–557 Uses of adrenal scintigraphy Adrenocortical Distinguishing unilateral from bilateral adrenocortical disease Autonomous asymmetric, bilateral adrenal hyperplasia in hypercortisolism (NP-59, SMC) Subtle bilateral adrenal hyperplasia in primary aldosteronism (NP-59, SMC) Identifying the adrenal contribution to hyperandrogenism (NP-59) Depicting adrenal cortical function Identifying function in benign vs space-occupying/malignant or metastatic unilateral and bilateral incidentally discovered adrenal masses (NP-59, SMC, FDG, MTO) Identifying function in adrenocortical reimplants after bilateral adrenalectomy (NP-59, SMC) Identifying adrenocortical function after intra-arterial alcohol infusion for ablation (NP-59, SMC) Preoperative identification of suppression of normal contralateral adrenal function (NP-59, SMC) Prediction of incidentally discovered masses with potential to progress to autonomous adrenal function (NP-59, SMC) Adrenomedullary Depicting sources of hypercatecholaminemia Intra-adrenal/extra-adrenal/metastatic/familial pheochromocytomas (MIBG, OCT, FDG, EPI, HED, DA, DOPA) Other neuroendocrine neoplasms Neuroblastoma, non-hypersecretory pheochromocytoma/paragangliomas (MIBG, OCT, FDG, EPI, HED, DA, DOPA)

teristics, specific radiopharmaceuticals can be used not only to measure the process of accumulation, but to depict target tissue endocrine function. In this manner, scintigraphy continues to play a role in the diagnosis and staging of malignant adrenal neoplasms, this role having evolved with the availability of PET and SPECT/CT [6–8]. In this paper we shall review recent developments in the field of adrenal scintigraphy that demonstrate again the importance of an approach that integrates the functional and anatomic evaluation of adrenal disease.

Physiologic basis of functional adrenal imaging The adrenal gland consists of two embryologically, morphologically and functionally distinct divisions, the adrenal cortex arising from mesoderm forming an outer zona glomerulosa producing mineralocorticoids (aldosterone) and a deeper zona fasciculata and reticularis producing glucocorticoids and weak androgens, and the adrenal medulla, arising from the neural crest, which secretes catecholamines. Adrenal cortex Steroid hormone biosynthesis begins with circulating lowdensity lipoprotein (LDL)-derived cholesterol, and it is this pathway that has been exploited with tracers that mimic cholesterol substrate, radiolabeled LDL or inhibitors of enzymes responsible for steroid hormone production. The

radiocholesterol analogues labeled with 131I or 75Se 6β-norcholesterols are rapidly incorporated into LDL and accumulated by adrenocortical steroid hormone-producing cells via a specific, receptor-mediated process. Within adrenocortical cells these radiocholesterols are esterified, but do not undergo further metabolism [9]. The adrenocortical LDL receptor is under the control of pituitary adrenocorticotrophic hormone (ACTH) in the zona fasciculata and reticularis and the renin-angiotensin system in the zona glomerulosa, and the accumulation of radiocholesterol analogs can be quantitatively related to steroid hormone output from the functional zones of the adrenal [9, 10]. Imaging protocols have been devised to take advantage of these mechanisms of control to accentuate abnormal function for improved diagnostic performance. Alternative approaches to adrenocortical scintigraphy are radiolabeled LDL and inhibitors of intermediary enzymes that participate in steroid biosynthesis. The recent introduction of 11Cmetomidate (MTO), a compound that binds selectively to 11β-hydroxylase (an enzyme essential in the biosynthesis of cortisol and aldosterone) and is regulated by ACTH, has been shown to depict adrenocortical neoplasms using PET [11–13] (Table 2). Adrenal medulla The adrenal medulla synthesizes catecholamines (norepinephrine and epinephrine) and stores them in membranebound vesicles. Control of catecholamine secretion is via

Eur J Nucl Med Mol Imaging (2007) 34:547–557 Table 2 Radiopharmaceuticals for adrenocortical scintigraphy

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Radiopharmaceutical

Metabolic activity

Target(s)/mechanism(s) of uptake

131

F-FDG

Uptake mediated receptor Uptake mediated receptor Uptake mediated receptor Uptake mediated receptor Uptake mediated receptor Glucose analog

11

C-acetate

TCA cycle intermediatea

11

Enzyme inhibitor Enzyme inhibitor Enzyme inhibitor

Adrenal cortex via the LDL receptor Adrenal cortex via the LDL receptor Adrenal cortex via the LDL receptor Adrenal cortex via the LDL receptor Adrenal cortex via the LDL receptor Glucose transport/metabolic intermediate Glucose transport/metabolic intermediate Adrenal cortical enzyme inhibitor Adrenal cortical enzyme inhibitor Adrenal cortical enzyme inhibitor

I-19-iodocholesterol

131

I-6-iodocholesterol

131

I-6β-iodomethylnorcholesterol

75

Se-selenomethylnorcholesterol

131

I,

Modified and used with permission from [2]: Gross MD, Rubello D, Shapiro B. Is there a future for adrenal scintigraphy? Nucl Med Commun 2002;23:197–202 LDL low-density lipoprotein, FDG fluorodeoxyglucose, TCA tricarboxylic acid

123

I,

111

In,

99m

Tc-LDL

18

C-etomidate C-metomidate 131 I-metyrapone 11

neural or humoral (e.g., angiotensin, serotonin, histamine) stimulation. Catecholamines are released from the vesicles by exocytosis and diffuse into the circulation, while in the adrenal medulla, catecholamines are subject to reuptake into secretory vesicles by a specific, energy-dependent, uptake mechanism (type I). Circulating catecholamines are inactivated by a type II uptake mechanism in extra-adrenal tissues and are rapidly metabolized to metanephrines. Metaiodobenzylguanidine (MIBG), a guanethidine analog structurally similar to norepinephrine (NE), is accumulated in the adrenal medulla by the type I uptake mechanism and is accumulated in the catecholamine storage vesicles, providing the rational for its use as a tracer for imaging sympathomimetic tissues [14–16]. Somatostatin receptors are widely distributed and are found in many neoplasms of the neural crest, and a growing number of somatostatin receptor imaging agents have demonstrated success in depicting neoplasms of adrenal medulla origin. Pentetreotide, a long-acting somatostatin antagonist, has been labeled with a variety of radioisotopes (e.g., 111In, 123I) and has been used to image pheochromocytomas and related neoplasms [17–19]. Like 131I- and 125 I-MIBG, somatostatin analogs labeled with alpha- and beta-emitters have been offered as alternatives or adjuncts to conventional chemotherapy for the treatment of metastatic pheochromocytomas, and beta-emitting analogs labeled with Y and Lu have been used in early clinical trials [20] (Table 3). There is a growing list of positron-emitting radiopharmaceuticals that target catecholamine synthesis or reuptake pathways to include: 11C-epinephrine, 11Chydroxyepinephrine, 18F-fluorodopamine and 18F-fluorodihydroxyphenylalanine. Taking advantage of the unique

by LDL by LDL by LDL by LDL by LDL

characteristics of adrenal medulla physiology, these agents have been demonstrated to have high sensitivity and specificity for localization of pheochromocytomas [17, 21]. 18F-fluoro-2-deoxy-D-glucose (18F-FDG), a non-specific tumor imaging agent, has been used to depict and stage a broad spectrum of neoplasms, including primary and metastatic adrenal tumors, with high sensitivity and specificity [22, 23].

Functional imaging of the adrenal cortex Cushing syndrome The availability of sensitive ACTH assays and the routine use of anatomic imaging techniques for detection of pituitary adenomas and other ACTH-secreting tumors have reduced the need for scintigraphy in the diagnosis of ACTH-dependent Cushing syndrome. Anatomic imaging in ACTH-dependent Cushing syndrome may show normal adrenals (in approximately 30% of cases) or diffuse bilateral enlargement (in approximately 70% of cases), and the mean width of the adrenal limbs is positively correlated with circulating cortisol and ACTH levels [24]. Iodocholesterol scintigraphy has, however, been used for identification of adrenal remnants in patients with persistent cortisol excess after bilateral adrenalectomy [5]. Primary adrenal disease causing ACTH-independent Cushing syndrome is most often the result of an adrenal adenoma, or uncommonly a hypersecreting, adrenal carcinoma or bilateral cortical nodular hyperplasia. Scintigraphy depicts each of these with a distinctive pattern. Adrenal adenomas display unilateral activity on scintigraphy as a

550 Table 3 Radiopharmaceuticals for adrenomedullary scintigraphy

Eur J Nucl Med Mol Imaging (2007) 34:547–557

Radiopharmaceutical

Metabolic activity

Target(s)/mechanism(s) of uptake

123

I-Tyr3-octreotide In-/111In-DOTA-Tyr3-octreotidea,b 90 Y-DOTA-Tyr3-octreotidea,b 86 Y-DOTA-Tyr3-octreotidea,b 114m In-octreotideb 90 Y-DOTA-lanreotidea,b 111 In-/111In-DOTA-lanreotidea,b 99m Tc-HYNIC-Tyr3-octreotide 123 I-VIP 123 I-MIBG

Somatostatin analog Somatostatin analog Somatostatin analog Somatostatin analog Somatostatin analog Somatostatin analog Somatostatin analog Somatostatin analog Hormone Neuronal blocker

131

Neuronal blocker

125

Neuronal blocker

131

Neuronal blocker

11

Catecholamine

11

Catecholamine analog Catecholamine analog Catecholamine

Neuroendocrine via somatostatin receptor Neuroendocrine via somatostatin receptor Neuroendocrine via somatostatin receptor Neuroendocrine via somatostatin receptor Neuroendocrine via somatostatin receptor Neuroendocrine via somatostatin receptor Neuroendocrine via somatostatin receptor Neuroendocrine via somatostatin receptor Neuroendocrine via VIP receptor Neuroendocrine via active transport into neurosecretory granules Neuroendocrine via active transport into neurosecretory granules Neuroendocrine via active transport into neurosecretory granules Neuroendocrine via active transport into neurosecretory granules Neuroendocrine via active transport into neurosecretory granules Neuroendocrine via active transport into neurosecretory granules Neuroendocrine via active transport into neurosecretory granules Neuroendocrine via active transport into neurosecretory granules Neuroendocrine via active transport into neurosecretory granules Glucose transport/metabolic intermediate

111

I-MIBGa

Modified and used with permission from [2]: Gross MD, Rubello D, Shapiro B. Is there a future for adrenal scintigraphy? Nucl Med Commun 2002;23:197–202 VIP vasoactive intestinal peptide, MIBG metaiodobenzylguanidine, AIBG aminoiod ob e n z y l g u a n i d i n e , H ED hydroxyephedrine, FDG fluorodeoxyglucose a Therapeutic or potential therapeutic radiopharmaceutical b Tricarboxylic acid cycle intermediate

I-MIBGa I-AIBGa

C-epinephrine C-hydroxyephedrine

11

C-phenylephrine

18

F-dopamine

18

Catecholamine

18

Glucose analog

F-dihydroxyphenylalanine F-FDG

result of suppression of ACTH and tracer accumulation in the contralateral, normal adrenal cortex [9, 25]. Bilateral cortical nodular hyperplasia, on the other hand, demonstrates bilateral uptake that is often asymmetric, reflecting the nodular process whereby large nodules are usually present in one gland with smaller nodules in the other. Functioning (hypersecreting) adrenocortical carcinomas usually do not image as a result of insufficient tracer accumulation by the tumor despite obvious Cushing syndrome with suppression of ACTH and contralateral adrenal accumulation of radiocholesterol [7, 9, 10]. The degree of cellular differentiation appears to play a role in the scintigraphic imaging of adrenal carcinoma, and there are reports of well-differentiated tumors that have imaged with NP-59 [26]. The clinical value of scintigraphy in ACTH-independent Cushing syndrome is to distinguish unilateral adenoma from bilateral cortical nodular hyperplasia, a distinction that may not be apparent biochemically or on high-resolution anatomic imaging; in this application, iodocholesterol scintigraphy has been shown to demonstrate high sensitivity and accuracy [26]. An alternative approach to adrenocortical imaging with radiocholesterol is PET with 11C-MTO [11–13, 27]. Recent

studies demonstrate that 11C-MTO can be used to distinguish adrenocortical neoplasms (including non-secreting and hypersecretory cortical adenomas, cortical carcinoma, and macronodular hyperplasia) from non-adrenocortical tumors (benign and malignant pheochromocytoma and metastasis to the adrenal) with high specificity (89%) and sensitivity (96%) [28]. On the other hand, 11C-MTO PET does not distinguish benign adrenal neoplasms from adrenocortical carcinoma [12, 27, 28]. It is interesting, however, that maximal SUVs in hypersecreting adrenal adenomas and an adrenocortical carcinoma were found to be greater than in the contralateral, normal adrenal cortex, indicating relative “suppression” of contralateral adrenal 11β-hydroxylase activity [12]. This is an expected consequence of uncontrolled unilateral hyperfunction upon pituitary ACTH, a condition that mimics the suppression of radiocholesterol uptake by the normal contralateral, adrenal cortex in hypersecreting adrenal adenomas in ACTH-independent Cushing syndrome [12]. A further alternative approach is to use 18F-FDG, which has been reported to depict both primary and metastatic adrenocortical carcinomas and some adrenocortical adenomas and bilateral adrenal hyperplasia [13, 24, 29–32].

Eur J Nucl Med Mol Imaging (2007) 34:547–557

Primary aldosteronism Hypersecretion of aldosterone from either an adrenal adenoma or bilateral adrenal hyperplasia characterizes the syndrome of primary aldosteronism. Excessive aldosterone secretion suppresses plasma renin activity and results in hypertension, hypokalemia and elevated plasma and urinary aldosterone levels. As a result of different secretory rates of the inner and the outer adrenal cortex, suppression of the ACTHdependent component of radiocholesterol uptake of the inner cortex with dexamethasone facilitates imaging and improves the diagnostic efficacy of iodocholesterol scintigraphy in evaluating the outer cortex in primary aldosteronism. Bilateral adrenal hyperplasia can be distinguished from unilateral adrenal adenoma and normal adrenal function based upon the pattern of imaging, i.e., unilateral vs bilateral, and the timing of adrenal visualization [9] (Fig. 1). With attention to details of concurrent medications that might interfere with adrenal function and subsequent iodocholesterol accumulation, studies performed under dexamethasone suppression demonstrate high sensitivity and specificity in primary aldosteronism [9]. Imaging protocols and interpretative algorithms using iodocholesterol do, however, require prolonged intervals after injection, and sometimes multiple imaging sessions. The utility of PET with 11C-MTO has been reported in five patients with primary aldosteronism due to adrenal adenoma. SUVs in the abnormal adrenals ranged from 15.7 to 22.0, although the ratio of maximal SUV of the

Fig. 1 NP-59 SPECT/CT in a 65-year-old man with primary hyperaldosteronism (Conn’s syndrome). A 0.8-cm left adrenal nodule is seen on a diagnostic CT scan (left). The scintigraphic images (middle)

551

hyperfunctioning gland to that of the contralateral normal gland was 1.2 with a range of 0.9–1.7. This reflects the lack of suppression of 11β-hydroxylase activity and contrasts with the higher adenoma/normal adrenal SUV ratios that favor Cushing’s adenoma and hypersecreting adrenocortical carcinoma [13]. Incidentally discovered adrenal masses (adrenal incidentaloma) The routine use of high-resolution imaging techniques (ultrasound, CT, and MR imaging) for evaluation of abdominal symptoms has led to the identification of many unsuspected adrenal lesions (incidentalomas) [22]. Multiple studies have shown that adrenal adenomas are common (2– 9%) in the general population. In the absence of a known malignancy, 70–94% of adrenal incidentalomas are nonhypersecreting, benign adenomas, while in the setting of a known extra-adrenal malignancy, 50% are adrenal metastases from carcinomas of the lung, breast, stomach, ovary, or kidney or from leukemia, lymphoma, or melanoma [33]. Other common adrenal masses are adrenal cysts (4–22%), myelolipoma (7–15%), and pheochromocytoma (0–11%) [34]. Regardless of the potential etiology, a biochemical evaluation sufficient to exclude a hypersecreting adrenal mass is mandatory. Although the extent of the biochemical evaluation remains a topic of disagreement, at a minimum it should include a representative functional analysis of all zones of the adrenal cortex and medulla.

demonstrate bilateral tracer activity (arrows) corresponding to the adrenal glands in an imaging pattern consistent with bilateral hyperplasia. The fused images are shown on the right

552

Computed tomography and MR imaging usually provide key anatomic clues in the characterization of incidentally discovered adrenal masses. Unenhanced CT density measurements of 10 HU. Intravenous contrast-provoked hypertensive crises, previously a source of concern, have not been seen with the use of non-ionic IV contrast agents, and contrast-enhanced CT in pheochromocytoma usually shows inhomogeneous enhancement of a solid mass, the findings being similar to those seen in adrenal metastasis or adrenal cortical carcinoma [37]. MR imaging has assumed a prominent role in imaging pheochromocytoma owing to its ability to define anatomic detail and tissue characterization. Most pheochromocytomas are hypointense on T1-weighted images and hyperintense on T2-weighted images. Although pheochromocytomas can be characterized by their hyperintensity on T2-weighted images, there is overlap with other neoplasms, e.g., adrenal cortical carcinomas, in up to 33% of cases [43]. Scintigraphy has played, and continues to play, an important role in imaging pheochromocytoma. MIBG

Eur J Nucl Med Mol Imaging (2007) 34:547–557

scintigraphy (using 131I or 123I with SPECT) and PET using F-fluorodopamine (18F-DA), 18F-dihydroxyphenylalanine 18 ( F-DOPA), 11C-epinephrine, and 11C-hydroxyephedrine have been demonstrated to image adrenomedullary neoplasms [6, 7, 17, 23, 44]. Regardless of the radioisotope, the patterns of imaging with these radiopharmaceuticals are essentially the same. Sporadic intra-adrenal pheochromocytomas are depicted as intense focal collections of radioactivity. MIBG scintigraphy has been particularly useful in imaging metastases and in the localization of extra-adrenal pheochromocytomas (Fig. 4). These lesions are often not detected by CT or MR imaging owing to their small size and their close relationship to other structures [45]. MIBG scintigraphy has a reported sensitivity of 87% and specificity of 99% for the detection of pheochromocytomas [15]. Radiolabeled octreotide has been successfully used to image pheochromocytomas and metastases with an efficacy that is less than that of MIBG for intra-adrenal pheochromocytoma but somewhat better for extra-adrenal and metastatic pheochromocytoma [17, 19, 20]. Thenormal distribution of MIBG includes the salivary glands, heart, liver, colon, bladder, and,in the case of 123I-MIBG, the normal adrenal medulla in approximately 20% of patients(vs
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