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Nuclear Medicine Communications

Role of positron emission tomography/computed tomography in adrenal and neuroendocrine tumors: fluorodeoxyglucose and nonfluorodeoxyglucose tracers

Ka Kit Wonga,b, Mohammad Arabia, Imene Zerizer“, Adil Al-Nahhas”, Domenico Rubellod and Milton D. Grossa,b

Positron emission tomography (PET) has seen an increasing clinical utilization in the last decade, such that it is now a standard oncology imaging modality. Its success is based on the detection of altered fluorine-18 fluorodeoxyglucose (18F-FDG) biodistribution, reflecting glucose transport/metabolism in malignant tumor tissues. Integrated PET/computed tomography cameras combine functional and anatomical information in a synergistic manner that improves diagnostic interpretation, and newer positron-emitting radiopharmaceuticals have been developed to expand the application of non-FDG PET imaging. The increasing use of cross-sectional imaging procedures has led to a more frequent detection of incidental adrenal masses. Although conventional imaging modalities such as computed tomography and MRI can characterize the majority of these lesions, 18F-FDG PET has been reported as a useful tool to distinguish benign from malignant etiologies in indeterminate adrenal masses. Although 18F-FDG PET has enjoyed success in staging a wide range of cancers, including detection of adrenal metastases and evaluation of adrenocortical carcinoma, it has had limited impact for the evaluation of neuroendocrine tumors. Positron-emitting amine precursor and somatostatin analogs have been validated in research

settings to provide accurate imaging of enterochromaffin and chromaffin neuroendocrine tumors and medullary thyroid cancer. The aim of this review article is to provide an overview of the role of 18F-FDG and newer positron- emitting radiopharmaceuticals in the evaluation of adrenal and neuroendocrine tumors. Nucl Med Commun 32:764-781 @ 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Nuclear Medicine Communications 2011, 32:764-781

Keywords: 11C-metomidate, 18F-dihydroxyphenylalanine 18F-fluorodeoxyglucose, 68Ga-DOTA peptides, adrenal incidentaloma neuroendocrine tumors, positron emission tomography/computed tomography

ªDepartment of Nuclear Medicine/Radiology, University of Michigan Hospital, bDepartment of Veterans Affairs Health System, Nuclear Medicine Service, Michigan, USA, “Department of Nuclear Medicine, Imperial College NHS Trust, Hammersmith Hospital, London, UK and ªDepartment of Nuclear Medicine, ‘Santa Maria della Misericordia Hospital’, Rovigo, Italy

Correspondence to Dr Adil Al-Nahhas, FRCP, Chief Service of Nuclear Medicine, Department of Nuclear Medicine, Imperial College NHS Trust, Hammersmith Hospital, Du Cane Road, London W12 OHS, UK

Tel: +44 208 3834923; fax: +44 208 3831700; e-mail: adil.al-nahhas@imperial.nhs.uk

Received 29 January 2011 Revised 13 March 2011 Accepted 24 March 2011

Introduction

The past decade has seen an increasing clinical utilization of positron emission tomography (PET), such that it is now considered a standard oncology imaging modality. Integrated PET/computed tomography (CT) cameras synergistically combine functional and anatomical infor- mation and have virtually replaced older, stand-alone PET cameras. Fluorine-18 fluorodeoxyglucose (18F-FDG) PET has been used successfully for detection of adrenal metastases and for staging of adrenocortical cancer. Newer positron-emitting radiopharmaceuticals adapted from corresponding single-photon emission computed tomography analogs show potential for accurate imaging of enterochromaffin and chromaffin neuroendocrine tumors (NETs), and medullary thyroid cancer (MTC). In particular, PET radiotracers such as 18F-dihydro- xyphenylalanine (18F-DOPA) and 68Ga-1,4,7,10-tetra- azacyclododecane-1,4,7,10-tetra-acetic acid (DOTA)

peptides are being increasingly used in routine clinical practice.

The increasing incidence of adrenal incidentalomas is directly related to the higher volume of cross-sectional imaging performed [1,2]. Crucial to the workup of these adrenal masses is the determination of their etiology, to exclude malignancy, either primary or secondary, and the identification of hypersecretory hormonal syndromes [3-5]. Although anatomical-based CT and MRI can characterize the majority of these masses as benign adrenal cortical adenomas (ACA), 18F-FDG PET can distinguish benign from malignant etiology in indetermi- nate masses, and can guide the subsequent management.

The aim of our review is to provide an update and overview of the role of 18F-FDG and newer positron- emitting radiopharmaceuticals for imaging of adrenal tumors and neuroendocrine tumors.

Positron-emitting radiotracers for adrenal and neuroendocrine tumor imaging 18F-fluoro-2-deoxy-D-glucose (glucose metabolism)

18F-FDG is the most widely utilized PET radiotracer in clinical use today and its properties and biodistribution have been extensively described. In brief, 18F-FDG is a glucose analog accumulated in tumors with overexpres- sion of glucose (Glut 1-7) transporters and phosphory- lated by hexokinase trapping intracellularly. Despite its obvious success, there are two limitations of 18F-FDG PET; first, it is nonspecific for neoplasms, with uptake by macrophages and other cells of the immune system; and second, neoplasms with low glucose metabolism, such as well-differentiated NETs, show poor FDG uptake reflecting the degree of tumor differentiation and biological behavior.

11C-metomidate and analogs (adrenal cortical imaging)

11C-etomidate, a key enzyme in the biosynthesis of cortisol and aldosterone, and its analog 11C-metomidate (MTO) have high uptake in the adrenal cortex and adrenal cortical tumors, allowing imaging of adrenal tumors in humans [6,7]. The short half-life of 11C (20 min) limits availability to centers with on-site cyclotron facilities and radiochemical synthesis capabil- ities, and methods of labeling MTO with 18F have recently been explored [8].

18F-fluorodihydroxyphenylalanine (sympathicomedullary imaging)

L-DOPA is an intermediate of the catecholamine synthesis pathway and its analog 6-L-18F-DOPA has been successfully used for imaging NETs. 18F-DOPA displays high uptake in NETs derived from amine precursor uptake and decarboxylation cells. Patients may be pretreated with oral carbidopa before 18F-DOPA PET imaging, which reduces the peripheral conversion of 18F-DOPA in liver and kidneys to metabolites such as 18F-fluorodopamine. Standardized uptake value (SUV) measurement of the adrenal uptake has been shown to have absolute thresholds for distinguishing normal adrenal uptake from pheochromocytoma [9].

Other PET radiotracers in this family include 11C-5- hydroxytryptophan (11C-HTP), 11C-hydroxyephedrine, 11C-epinephrine, and 18F-fluorodopamine. However, in comparison with 18F-DOPA, the radiosynthetic process for these radiotracers is more complex, which may ultimately limit their clinical application.

68 Ga-DOTA peptides (somatostatin receptor imaging)

Somatostatin analogs have affinity for G-protein-coupled membrane-bound somatostatin receptors (SSTR) sub- types 1-5, which are overexpressed in NETs [10,11]. Peptide-based imaging has the advantages of high specificity, rapid clearance, and low antigenicity [10]. In addition, peptide imaging provides evidence for targeting

of tumor tissue, which predicts therapeutic success with 90Y or 177 Lu radionuclide therapies.

68Ga is readily available from a germanium-68/gallium-68 generator, with the parent half-life of 270.8 days and an effective supply of 68Ga for 1 year. 68Ga is the first example of a clinically available PET agent that is not dependent on production using an on-site cyclotron. The radiolabeling process is relatively easy to perform with an estimated synthesis time of 25 min from elution to patient injection. Common 68Ga-DOTA-somatostatin analogs include 68Ga-DOTA-Tyr-3-octreotide, 68Ga- DOTA-NaI-octreotide (DOTANOC), and 68Ga-DOTA- octreotate (DOTATATE) with varying affinities for SSTR subtypes 1-5, which have slightly different imaging performance, but the results are unlikely to be of any clinical significance [11].

Positron emission tomography/computed tomography imaging of adrenal tumors Adrenal incidentaloma

The widespread use of cross-sectional anatomical imaging modalities such CT and MRI for the evaluation of nonadrenal disease has led to an increased detection of unsuspected, asymptomatic adrenal nodules, known as incidentalomas, in 4-10% of patients [3-5,12]. The majority of these adrenal nodules are benign and hormonally inactive. However, some of these masses will require surgical intervention, particularly if they are malignant or hormonally functional. Surgical adrenalect- omy based on size criteria of more than 4 cm will lead to the removal of benign adrenal masses in a proportion of patients. Therefore, further characterization of indeter- minate adrenal masses may guide further management, and studies reporting PET and PET/CT for the evalua- tion of adrenal masses are summarized in Table 1.

18F-fluorodeoxyglucose positron emission tomography and positron emission tomography/computed tomography

18F-FDG PET/CT for the evaluation of adrenal inciden- talomas in patients without a history of cancer has been reported to have high sensitivity of 89-100% and good specificity of 70-88% for detection of malignancy [30-34]. Similarly, in patients with known cancer undergoing 18F- FDG PET or PET/CT for cancer staging, adrenal uptake is not an uncommon finding, with high sensitivity of 74- 100% and good specificity of 66-100% for separating benign masses from adrenal metastases [13-29]. An example from our database is shown in Fig. 1.

The results of numerous studies show that 18F-FDG adrenal uptake has a highly positive predictive value for adrenal malignancy, regardless of the interpretation criteria chosen and whether the patient has earlier history of cancer or not (Fig. 2).

Table 1 Studies reporting positron emission tomography and positron emission tomography/computed tomography imaging of adrenal masses and tumors

References	Number of patients	Group	Modality	Sensitivity (%)	Specificity (%)	Comments
18F-FDG imaging of adrenal masses in oncology patients
Boland et al. [13]	20/24	Mixed cancer	18F-FDG PET	100	100	Adrenal SUV > background
Erasmus et al. [14]	27/33	Lung cancer	18F-FDG PET	100	80	Adrenal SUV > background
Gupta et al. [15]	30/30	Lung cancer	18F-FDG PET	94	91	Adrenal uptake ≥ liver
Yun et al. [16]	41/50	Mixed cancer	18F-FDG PET	100	94	Adrenal uptake ≥ liver
Kumar et al. [17]	94/113	Lung cancer	18F-FDG PET	93	90	Adrenal uptake > liver
Frilling et al. [18]	42/44	Mixed cancer	18F-FDG PET	100	66	Adrenal uptake ≥ liver
Jana et al. [19]	74/80	Mixed cancer	18F-FDG PET	93	96	Adrenal uptake > liver
				100	73	SUVmax >3.1
				95	86	SUVmax >3.4
Blake et al. [20]	40/40	Mixed cancer	18F-FDG PET/CT	100	93	Adrenal uptake > liver
Metser et al. [21]	150/175	Mixed cancer	18F-FDG PET, PET/CT	99	92	SUVmax >3.1
				100	93	SUVmax >3.1 and <10HU
Park et al. [22]	14/20	Mixed cancer	18F-FDG PET/CT	88	75	Adrenal uptake ≥ liver
			CECT	100	100
Vikram et al. [23]	96/112	Mixed cancer	18F-FDG PET/CT	83	85	Adrenal SUV average ≥ liver
Brady et al. [24]	147/187	Lung cancer	18F-FDG PET/CT	97	86	SUVmax >3.1 and HU >10 97%
				97	66	Adrenal:liver ratio > 1.0
				97	74	Adrenal:liver ratio > 1.0 and > 10 HU
Caoili et al. [25]	59/59	Mixed cancer	18F-FDG PET/CT	ACA	Non-ACA
				51	0	Adrenal uptake <liver
				38	25	Adrenal uptake =liver
				10	75	Adrenal uptake >liver
Sung et al. [26]	42/61	Lung cancer	18F-FDG PET	74	73
			18F-FDG PET/CT	80	89
Boland et al. [27]	150/165	Mixed cancer	18F-FDG PET/CT	100	97	Visualization
				100	94	SUVmax >2.3
				100	97	Adrenal:liver ratio > 1.8
			Unenhanced CT (>10 HU)	66	100
Okada et al. [28]	30/35	Mixed cancer	18F-FDG PET/CT	89	94	SUVmax >2.5
				85	100	Adrenal:liver ratio >1.8
			Unenhanced CT (>10 HU)	57	94
Gratz et al. [29]	109/109	Mixed cancer	18F-FDG PET/CT	97	94	Visualization
				95	94	SUVmax >2.3
				97	92	Tumor:liver ratio >1.0
			CECT	95	94
			Chemical-shift MR	97	92
18F-FDG imaging of adrenal masses in patients without cancer history
Maurea et al. [30]	27/27	Incidentaloma	18F-FDG PET	100	93	Adrenal SUV > background
Han et al. [31]	105/105	Incidentaloma	18F-FDG PET	94	83	Adrenal uptake ≥ liver
			Unenhanced CT (>10 HU)	88	69
Tessonnier et al. [32]	37/41	Incidentaloma	18F-FDG PET/CT	100	86	Visualization
				100	100	Adrenal:liver ratio >1.8
Groussin et al. [33]	77/77	Incidentaloma	18F-FDG PET/CT	100	88	Adrenal:liver ratio > 1.45
			ACA or ACC	100	70	SUVmax >3.4
Ansquer et al. [34]	78/81	Incidentaloma	18F-FDG PET/CT	73	97	Lesions requiring surgery
				89	76	Malignancy
18F-FDG imaging of ACC
Becherer et al. [35]	10	ACC	18F-FDG PET	100	95
Tenenbaum et al. [36]	3 of 13	ACC	18F-FDG PET	100	N/A
Mackie et al. [37]	12	ACC	18F-FDG PET/CT	83	N/A	2 false negative
Leboulleux et al. [38]	28	ACC	18F-FDG PET/CT	90	N/A	SUVmax uptake > 10 is a prognostic
						indicator
			CT	88	N/A
11C-MTO imaging of adrenal masses and ACC
Bergstrom et al. [6]	15	Mixed adrenal	11C-MTO PET	100	100	Cortical from nonadrenal
Khan et al. [39]	11	ACC	11C-MTO PET	72	N/A	ACA and ACC both have 11C-MTO uptake
Zettinig et al. [40]	16	Mixed adrenal	11C-MTO PET	N/A	N/A	11C-MTO uptake cannot separate
			18F-FDG PET/CT	N/A	N/A	benign from malignant masses
Minn et al. [41]	21	Incidentaloma	11C-MTO PET	N/A	N/A	11C-MTO uptake cannot separate
			18F-FDG PET/CT	N/A	N/A	benign from malignant masses
Hennings et al. [42]	173	Incidentaloma	11C-MTO PET	89	96	Adrenocortical versus nonadrenal
Hennings et al. [43]	44	Incidentaloma	CT	71	100	etiology Combination of CT/MRI with 11C-MTO
			MRI	86	100	PET has best performance
			CT, MRI, 11C-MTO PET	100	100

ACA, adrenal cortical adenoma; ACC, adrenocortical cancer; 11C-MTO, 11C-metomidate; CECT, contrast-enhanced CT; CT, computed tomography; 18F-FDG, fluorine-18 fluorodeoxyglucose; HU, Hounsfield units; MRI, magnetic resonance imaging; PET, positron emission tomography; SUVmax, maximum standardized uptake value.

Fig. 1

(a)

(b)

(c)

18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) study in a 62-year-old man with colorectal carcinoma with liver and peritoneal metastases. Axial PET (a), fused PET/CT (b), and nonfused CT (c) images demonstrate a 3 cm left adrenal lesion (arrows) with Hounsfield unit of 10 with mild FDG uptake less than the liver background, lesion maximum standardized uptake value (SUV) of 1.8 compared with the liver SUV mean of 3.3, compatible with a lipid-rich adenoma.

Fig. 2

(a)

298%

H/L 5.3/00

509%

(b)

215/410

V1-Transavial

WAL 400/30: HA. 5.3/00 :

227%

(c)

V1-Rendered

215/410

V2N/1-T100said

18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) study for staging of lung cancer. Maximum intensity projection (a), axial PET (b), and fused PET/CT (c) images show thickening of the right adrenal gland (arrows) with an increased FDG uptake of similar intensity to the primary left lower lobe tumor. The adrenal maximum standardized uptake value (SUV) of 28 compared with the liver background SUV mean of 2.6 is compatible with metastatic disease to the adrenal gland, in the presence of widespread metastases.

An increased adrenal FDG uptake as a result of inflammation (e.g. granulomatous disease) and infection will confound diagnosis leading to false-positive results [34]. In addition, a small proportion of benign ACAs may show FDG uptake greater than the liver background,

often but not always in secretory masses (Fig. 3). Benign pheochromocytoma will also display an increased adrenal FDG uptake and should be considered in the presence of elevated catecholamine levels. Conversely, false-negative results have been recognized to occur due to small lesion

Fig. 3

(a)

(b)

(c)

18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) study in a 62-year-old woman with a history of Hurthle cell carcinoma. Maximum intensity projection (a), coronal PET (b), and fused PET/CT (c) show a left adrenal mass (arrows) with intense FDG uptake similar to a proven metastatic lesion in the left humerus. The adrenal mass demonstrated low attenuation on the CT scan with <10 HU. The measured maximum standardized uptake value (SUV) was 7.1 compared with the mediastinal blood pool background SUV mean of 1.8 meeting the metabolic criteria for adrenal metastasis. However, after left adrenalectomy, histopathology confirmed the diagnosis of adrenal cortical adenoma.

size (<8 mm), certain cancer types with low FDG avidity (e.g. renal cell cancer, NETs, etc.), tumor necrosis, and in adrenal metastases resulting from previous chemotherapy effect upon tumor glucose transport [23]. An example from our database is shown in Fig. 4.

CT, MRI, and PET/CT demonstrate efficacy in char- acterization of adrenal masses. In two studies, PET/CT has been reported to have superior diagnostic perfor- mance compared with unenhanced CT, mainly due to limited sensitivity of unenhanced CT for lipid-poor adenomas, despite showing good specificity [27,28]. Several studies of patients without history of cancer include indeterminate adrenal masses on CT or MRI in which 18F-FDG PET/CT was able to further characterize these adrenal masses accurately [32-34]. PET/CT has been reported to be less accurate than contrast-enhanced CT using washout criteria in one study [22] and to be similar in diagnostic performance to contrast-enhanced CT and MRI in another study [29]. PET/CT performs better than stand-alone PET [21,26], and the combination

of PET diagnostic criteria with lesion-attenuation char- acteristics on the unenhanced CT (usually Hounsfield units < 10) has been shown to improve accuracy over either criterion alone [21,24].

Nonfluorodeoxyglucose positron emission tomography/ computed tomography

In suspected sympathomedullary tumors, 18F-DOPA could potentially be used to characterize adrenal masses due to its high specificity for NETs and pheochromocy- tomas. 68Ga-DOTA peptide imaging may have a limited role in the workup of adrenal masses, due to the high somatostatin receptor expression in the normal adrenal gland and at sites of infection or chronic granulomatous inflammation leading to potential false positives.

The use of 11C-MTO PET in the evaluation of adrenal incidentalomas has been reported [6,7,40-43]. Bergstrom et al. [6] noted 100% sensitivity and specificity of 11C-MTO PET for identifying adrenocortical versus

Fig. 4

(a)

(b)

(c)

18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in a 64-year-old man with a history of renal cell carcinoma and a growing right adrenal nodule. Maximum intensity projection image (a), corresponding axial PET (b), and fused PET/CT (c), demonstrate a mildly metabolically active right adrenal nodule (arrows) with a maximum standardized uptake value (SUV)=2.6 compared with liver background (SUV mean=1.7). However, as renal cell cancer is known to have low FDG avidity, and the nodule was growing, right laparoscopic adrenalectomy was performed with histopathology specimen compatible with metastatic renal cell cancer.

nonadrenal masses, with both ACA and adrenocortical carcinoma (ACC) showing high 11C-MTO uptake.

In a study of 212 patients, 11C-MTO PET had sensitivity of 89% and specificity of 96% for distinguishing adrenocortical from nonadrenocortical masses. The up- take of 11C-MTO does not seem to be dependent on functional status as there was no suppression of 11C- MTO uptake in the contralateral gland due to hyperse- cretory adrenal tumors [42]. In another study of 44 patients with unilateral adrenal masses, the addition of 11C-MTO to morphological imaging improved sensitivity of CT (71%) and MRI (86%) to 100% [43].

Adrenocortical cancer

ACC is a rare malignancy with a poor prognosis, characterized by advanced stage at diagnosis and overall 5-year survival of 20-45% or less than 12% in the presence of distant metastases [44]. Primary treatment is adrena- lectomy with mitotane reserved as an adjuvant treatment. Recurrence rates at 2 years are high at 73-86% despite

complete surgical resection, and as a result, imaging strategies are used to detect recurrences early in an attempt to improve survival [44].

18F-fluorodeoxyglucose positron emission tomography/ computed tomography

18F-FDG PET and PET/CT have been reported for staging and restaging ACC in both adults and children (Fig. 5). Tenenbaum et al. [36] found 18F-FDG PET correctly identified three ACCs and one adrenal metas- tasis, whereas nine benign lesions did not have significant FDG uptake. Becherer et al. [35] reported that in 10 patients with ACC, 18F-FDG PET had a sensitivity of 100% and specificity of 95%. Mackie et al. [37] found that 18F-FDG PET/CT correctly identified all sites of disease in 10 of 12 patients; however, false-negative findings were reported in two patients with small pulmonary and hepatic metastases.

In the largest study to date, Leboulleux et al. [38] reported the use of 18F-FDG PET/CT compared with CT

Fig. 5

(a)

(b)

(d)

(c)

(e)

18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) study in a 42-year-old man with a history of bilateral adrenal lesions diagnosed on abdominal CT scan. Maximum intensity projection image (a), corresponding axial (b and c), and coronal PET and fused PET/CT (d and e) demonstrate large bilateral heterogeneous centrally necrotic adrenal masses (arrows). The left adrenal mass demonstrates maximum standardized uptake value (SUV) of 49 compared with the liver background SUV mean of 1.6, meeting the metabolic criteria for adrenal neoplasm. Lymphoma or lung metastases were considered in the differential diagnosis; however, core biopsy specimens of the left adrenal lesion were consistent with adrenocortical carcinoma, with a rare bilateral presentation.

alone in 28 patients with ACC. A total of 269 lesions were detected in 22 patients. 18F-FDG PET/CT had a sensitivity of 90% similar to diagnostic CT (88%). Twelve percent of lesions were seen on PET/CT only and 10% on CT only, suggesting that these two modalities are complementary. Analysis of survival in a subgroup of 21 patients found FDG maximum SUV (SUVmax) of more than 10 to be an adverse prognostic factor at 6 months.

11C-metomidate positron emission tomography

ACC has been shown to demonstrate an increased uptake of 11C-MTO, allowing imaging of the primary neoplasm and metastatic disease [6,7,39-41,45]. However, 11C- MTO cannot distinguish between ACC and ACA based on the uptake alone. In a study of 11 patients with ACC, 11C-MTO PET had a sensitivity of 72% (8/11) [39]. False-negative studies occurred due to tumor necrosis in three patients; therefore, 18F-FDG PET/CT remains the radiotracer of choice for staging ACC.

Positron emission tomography/computed tomography imaging of neuroendocrine tumors

Enterochromaffin neuroendocrine tumors

NETs are a rare, heterogeneous group of neoplasms derived from endocrine stem cells of the amine precursor uptake and decarboxylation system. They share the ability to accumulate and decarboxylate amine precursors such as L-DOPA and 5-HTP causing pronounced clinical symptoms due to secretion of biogenic amines and polypeptides [46]. Metastatic disease at diagnosis is

frequent and detection with conventional anatomical imaging is problematic due to the small size of lesions.

The older classification system of NETs as either carcinoid (50% of NETs) and noncarcinoid tumors based on classical symptoms of flushing, hypotension, and diarrhea has been replaced by classification based on tumor size and proliferation rate. Type 1a NETs are well- differentiated tumors (Ki-67 < 2%) or type 1b carcino- mas (Ki-67 2-10%) and type 2 NETs are poorly differentiated carcinomas.

Studies reporting PET and PET/CT for the evaluation of enterochromaffin NETs are summarized in Table 2.

18F-fluorodeoxyglucose positron emission tomography and positron emission tomography/computed tomography

In contrast to its success in imaging solid and lymphoid malignancies, 18F-FDG PET was recognized as being of low avidity for well-differentiated NETs [47]. Pasquali et al. [49] evaluated 18F-FDG PET in 16 patients with carcinoids. For aggressive NETs, 18F-FDG PET was positive for the primary site in all patients; however, for slow-growing NETs, 18F-FDG PET was negative in seven patients and weakly positive in one patient. Furthermore, in a group of 17 patients consisting solely of carcinoid tumors mainly with low-proliferative Ki-67 indices, 18F- FDG PET was insensitive, leading the investigators to recommend reserving PET for patients with negative somatostatin receptor scintigraphy [50].

Table 2 Studies reporting positron emission tomography and positron emission tomography/computed tomography imaging of neuroendocrine tumors

References	Number of patients	Group	Modality	Sensitivity (%)	Specificity (%)	Comments
PET imaging of enterochromaffin NETs
18F-FDG imaging
Adams et al. [47,48]	7	GEPT	18F-FDG PET	43 (3/7 patients)	N/A	18F-FDG PET negative in well-differentiated NETS
Pasquali et al. [49]	16	NETs	18F-FDG PET	100 (8/8 patients)	N/A	Agressive NETs
			18F-FDG PET	13 (1/8 patients)	N/A	Slow-growing NETs
			SRS	85
Belhocine et al. [50]	17	Carcinoids	18F-FDG PET	57 (4/7 foci)	N/A	SRS superior to 18F-
						FDG
			SRS	86 (6/7 foci)	N/A
Garin et al. [51]	38	Low-grade NETs	18F-FDG PET, PET/CT	87	96	Predicting patients with
			SRS	56	91	progressive disease
Binderup et al. [52,53]	96	NETs	18F-FDG PET/CT	58	N/A	18F-FDG PET had
			MIBG	52	N/A	highest sensitivity
			SRS	89	N/A	(92%) for Ki-67 >15
18F-DOPA and amine precursor imaging
Ambrosini et al. [54]	13 of 84	NETs	18F-DOPA PET	13/13 patients	N/A	18F-DOPA PET
		CT/SRS negative				provided extra
						information in all patients
Koopmans et al. [55]	53	Carcinoid	18F-DOPA PET	100	N/A
			SRS, SPECT/CT	92, 96	N/A
			CT	87	N/A
Koopmans et al. [55]	24	Carcinoid	18F-DOPA PET/CT	98	N/A	Carcinoids
	23	Islet cell tumors	11C-5-HTP PET/CT	89	N/A	18F-DOPA superior
			18F-DOPA PET/CT	80	N/A	Islet cell tumors
			1C-5-HTP PET/CT	96	N/A	11C-5-HTP superior
Kauhanen et al. [56]	82	NETs	18F-DOPA PET	90	N/A	18F-DOPA PET first-line for staging, restaging NET
Haug et al. [57]	25	NETs	68Ga-DOTATATE PET	96	N/A	18F-DOPA correlates
		Metastatic	18F-DOPA PET	56	N/A	with serotonin levels
Schiesser et al. [58]	61	NETs	18F-DOPA PET/CT	91 (32/36 patients)	96
			SRS	59	86
68Ga-DOTA peptide imaging
Hofmann et al. [59]	8	Carcinoid	68 Ga-DOTA PET	100 (40/40 foci)		68Ga-DOTA superior to
			SRS	85		SRS
Koukouraki et al. [60]	22	NETs	68Ga-DOTA PET	90 (57/63 foci)		68Ga-DOTA superior to
			18F-FDG PET	68 (43/63 foci)		18F-FDG
Buchmann et al. [61]	27	NETs	68Ga-DOTA PET	Detected 279 foci in 81 regions		68Ga-DOTA superior to
						SRS
			SRS	Detected 152 foci in 54
				regions
Gabriel et al. [62]	88	NETs	68Ga-DOTA PET	97	92	68Ga-DOTA superior to
			SRS	52	92	SRS
			CT	61	71
Ambrosini et al. [63]	13	NETs	68Ga-DOTA PET	100 (13/13 patients)	N/A	68Ga-DOTA superior to
			18F-DOPA PET	69 (9/13 patients)	N/A	18F-DOPA
Fanti et al. [64]	14	Unusual sites	68Ga-DOTA PET	N/A	N/A	Useful in 7/14 patients
Kayani et al. [65]	38	NETs	68Ga-DOTA PET/CT	82	N/A	68Ga-DOTA superior to
			18F-FDG PET/CT	66	N/A	18F-FDG
Ambrosini et al. [11]	11	Bronchial	68Ga-DOTA PET	82% (9/11 patients)	N/A	Additional information- carcinoidto CT
Prasad et al. [66]	59	CUP-NET	68Ga-DOTA PET	59 (35/59 patients)	N/A	Localized primary site
Ambrosini et al. [67,68]	44 of 223	NETs bone	68 Ga-DOTA PET	100 (44/44 patients)	100
		metastases
			CT	80 (35/44 patients)	98
PET imaging of chromaffin NETs
18F-FDG imaging
Shulkin et al. [69]	29	Pheochromocytoma	18F-FDG PET	58 (7/12 patients) with
				benign pheochromo-
				cytoma
				885 (15/17 patients) with malignant pheochromocytoma
Timmers et al. [9,70]	30	Pheochromocytoma/ PGL	18F-FDG PET	100	N/A	18F-FDG PET superior
						for patients with
		SDHB mutations	18F-DA PET	88	N/A	SDHB associated
			MIBG	80	N/A	pheochromocytoma/
			SRS	81	N/A	PGL

Table 2 (continued)

References	Number of patients	Group	Modality	Sensitivity (%)	Specificity (%)	Comments
Taieb et al. [71]	9	Pheochromocytoma/ PGL	18F-FDG PET/CT	N/A	N/A	18F-DOPA feasible for head/neck PGL
			18F-DOPA PET/CT	N/A	N/A
Zelinka et al. [72]	71	Pheochromocytoma/	18F-DA PET	90	N/A	18F-FDG PET is
		PGL				preferred with
		Bone metastases	18F-FDG PET	76	N/A	SDHB mutations
			CT/MRI	78	N/A
Taieb et al. [73]	28	Pheochromocytoma/ PGL	18F-FDG PET/CT	93 (26/28 patients)	N/A	18F-FDG uptake is
						higher with SDHB
18F-DOPA and amine precursor imaging						mutations
Imani et al. [74]	25	Pheochromocytoma/ PGL	18F-DOPA PET, PET/CT	84	100
Fiebrich et al. [75]	48	Catécholamine	18F-DOPA PET	90	N/A	18F-DOPA PET superior
			CT/MRI	67	N/A	excess to CT/MRI/
			MIBG	65	N/A	MIBG
Luster et al. [76]	25	Pheochromocytoma	18F-DOPA PET/CT	100 (19/19 patients)	N/A
Fottner et al. [77]	30	Pheochromocytoma/	18F-DOPA PET	98 (62/64 foci)	100	MIBG negative when
		PGL				VMAT1 not expressed
			123MIBG	53 (34/64 foci)	91
Pacak et al. [78]	28	Pheochromocytoma	18F-DA PET	100 (8/8 patients)	82 (9/11
					patients)
Ilias et al. [79]	16	Pheochromocytoma	18F-DA PET	100 (16/16 patients)
			MIBG	44 (7/16 patients)
Ilias et al. [80]	53	Pheochromocytoma	18F-DA PET	90	75	18F-DA PET superior to
						MIBG
			MIBG	76	63
			SRS	22	74
Timmers et al. [81]	99	Pheochromocytoma	18F-DA PET	92	90
			123MIBG, 131MIBG	83, 70	100, 100
			CT	100	41
			MRI	98	60
68Ga-DOTA peptide imaging
Win et al. [82,83]	1	Pheochromocytoma	68Ga-DOTA PET	N/A	N/A	68Ga-DOTA uptake
						pheochromocytoma

CT, computed tomography; CUP-NET, carcinoma of unknown primary-neuroendocrine tumor; 18F-DA, 18F-dopamine; 18F-FDG, fluorine-18 fluorodeoxyglucose; 18F-DOPA, 18F-fluorodihydroxyphenylalaine; GEPT, gastroenteropancreatic tumor; MIBG, metaiodobenzylguanidine scintigraphy; N/A, not available; NETs, neuroendocrine tumors; PET, positron emission tomography; PGL, paraganglioma; SDHB, succinate dehydrogenase enzyme subunit B; SRS, somatostatin receptor scintigraphy.

More recent studies have focused on 18F-FDG PET/CT use in patients with aggressive, metastatic disease to determine metabolic prognostic features [51-53]. Garin et al. [51] prospectively evaluated 38 patients with low- grade NET using CT, somatostatin receptor scintigraphy (SRS), and 18F-FDG PET and PET/CT. Fourteen of 15 patients with positive PET had early progressive disease, whereas 21 of 23 patients with negative PET scans had stable disease. 18F-FDG PET SUV was found to be an independent predictive factor for progres- sion-free survival.

18F-dihydroxyphenylalanine positron emission tomography and positron emission tomography/ computed tomography

18F-DOPA PET and PET/CT have been shown to have high diagnostic accuracy for imaging NETs with rare false- positive results. Schiesser et al. [58] found 18F-DOPA had sensitivity of 91% and specificity of 96%, compared with SRS single-photon emission computed tomography with sensitivity of 59% and specificity of 86%, changing

management in 16% of patients with NETs. Another study of 53 patients with mixed NETs found 18F-DOPA had superior sensitivity of 100%, compared with CT of 87%, SRS of 92%, and SRS SPECT/CT of 96% [84]. In a study of patients with NETs and otherwise negative conventional imaging, 18F-DOPA PET/CT was able to identify primary lesions in all 13 patients [54]. Kauhanen et al. [56] reported in 82 patients that 18F-DOPA PET for staging of the primary tumor had a sensitivity of 88 and 92% for restaging.

Generally, 18F-DOPA PET has been found to be most sensitive in patients with functioning carcinoid tumors, with lower sensitivity for noncarcinoid NETs such as pancreatic islet cell tumors and MTC. Compared with 68Ga-DOTATATE, one study showed that 18F-DOPA had sensitivity of 56% (29/55 lesions), whereas 68Ga-DOTA- TATE had 96% sensitivity (54/55) [57]. An example from our database is shown in Fig. 6. Comparison of 18F-DOPA PET with 11C-5-HTP PET in patients with carcinoid and pancreatic islet cell tumors found that for carcinoid tumors 18F-DOPA PET/CT sensitivity was 98%, which

Fig. 6

(a)

(b)

(c)

68Ga-DOTATATE positron emission tomography (PET) maximum intensity projection image (a) in a patient with primary pancreatic head neuroectodermal tumor clearly shows multifocal liver metastases, which are more conspicuously depicted with PET in comparison with anterior (b) and posterior (c) whole-body planar 111In octreotide images, which show less and faintly avid metastatic liver lesions.

was superior to 11C-HTP PET/CT (89%). However, for pancreatic islet cell tumor, the results were reversed [55].

68 Ga-DOTA peptide positron emission tomography and positron emission tomography/computed tomography Enterochromaffin NETs have a characteristic high expression of SSTR inversely related to the degree of tumor differentiation. 68Ga-DOTA peptide PET has reported excellent sensitivities of 82-100% and specifi- cities of 92-100% for imaging NETs with detection rates exceeding standard SRS imaging agents [59,61,62,85]. In a large study of 84 patients with NETs, 68Ga-DOTA-Tyr- 3-octreotide PET had a sensitivity of 97%, and a specificity of 92%, which was superior to 99mTc-HYNIC octreotide (52 and 92%, respectively) and diagnostic CT (61 and 71%, respectively) [62]. Observations regarding the use of 68Ga-DOTA peptides have been extended to more specific subgroups of NET. 68Ga-DOTANOC has been investigated for very rare NETs in unusual sites [64] and also for evaluation of NET carcinoma of unknown origin localizing the primary site in 35 of 59 (59%) patients [66]. In a group of 11 patients with bronchial carcinoid, 68Ga-DOTANOC detected more sites of disease than CT in five patients and excluded malignancy in three patients falsely interpreted as disease on CT [11]. 68Ga-DOTANOC PET/CT seems to be superior to CT for detection of bone metastases with sensitivity and specificity of 100% compared with CT sensitivity of 80% and specificity of 98% [67].

In a comparison study of 68Ga-DOTA PET and 18F-FDG PET, 68Ga-DOTATATE PET had a sensitivity of 82% compared with a sensitivity of 66% for 18F-FDG PET

[86]. Another comparative study of 68Ga-DOTANOC and 18F-DOPA found that 68Ga-DOTANOC performed slightly better for differentiated NET. 68Ga-DOTANOC was positive in all 13 cases, whereas 18F-DOPA was positive in only nine of the 13 cases [63].

68Ga-DOTANOC uptake has been found to correlate with prognosis. In a study of 47 patients, a threshold SUV between 17.9 and 19.3 could be used to separate patients with regressing or stable disease compared with tumors with progression [87]. Another important use of 68Ga-DOTANOC PET has been to establish the SSTR status of lesions seen on CT, MRI, or ultrasono- graphy, as tumor uptake of 68Ga-DOTA suggests favorable response to treatment with long-acting soma- tostatin analogs or radionuclide-based peptide therapy [60].

Chromaffin neuroendocrine tumors

Sympathomedullary tumors are NETs derived from chromaffin cells, postganglionic sympathetic neurons that secrete catecholamine. The majority of these cells are located in the adrenal medulla or in an extra-adrenal location near the celiac axis. Chromaffin NETs arising in the adrenal gland are termed pheochromocytomas, whereas those arising from extra-adrenal tissues are paragangliomas (PGL).

Patients with chromaffin NETs usually present with hypertension and symptoms of biogenic amine excess. Pheochromocytoma occurs in 0.5% of patients with hypertension and in 4% of incidentally discovered adrenal incidentalomas. Genetic testing may be positive in 12-25% of apparently sporadic cases with association to hereditable

syndromes, including multiple endocrine neoplasia (MEN) type 1, neurofibromatosis type 2, von Hippel- Lindau syndrome, and tuberous sclerosis [88]. Studies reporting PET and PET/CT for the evaluation of enterochromaffin NETs are summarized in Table 2.

18F-fluorodeoxyglucose positron emission tomography and positron emission tomography/computed tomography

18F-FDG PET is useful for the assessment of benign and metastatic pheochromocytoma and PGLs [69-71,73]. Shulkin et al. [69] found 18F-FDG PET was positive in 22 of 29 (76%) patients with pheochromocytoma. Most benign pheochromocytoma (7/12 patients) and an even higher percent of malignant pheochromocytoma (15/17 patients) were FDG avid. Comparison with 123I-metaio- dobenzylguanidine (MIBG) scans showed that four patients with negative MIBG imaging had disease identified with 18F-FDG PET. However, in nine other patients, MIBG had superior target-to-background tumor uptake ratios. An example from our database is shown in Fig. 7.

Taieb et al. [73] investigated 28 patients with metastatic and nonmetastatic chromaffin-derived tumors, including nine patients with genetic syndromes, and found 18F- FDG PET-detected disease in 26 of 28 (92%) patients. Succinate dehydrogenase and von Hippel-Lindau-related tumors had higher FDG SUVmax than neurofibromatosis and MEN-related pheochromocytoma/PGL. 18F-FDG PET imaging has been found to be superior to 18F-DOPA PET for detection of adrenal and metastatic pheochro- mocytoma, whereas 18F-DOPA and MIBG imaging were more specific than 18F-FDG PET [71].

Timmers et al. [70] investigated 30 patients with succinate dehydrogenase subunit B (SDHB) germ line mutation with metastatic pheochromocytoma/PGL. Although not all patients were studied with each modality, 18F-FDG PET had a sensitivity of 100%, 18F- DOPA 88%, MIBG 80%, and SRS 81%. At least 90% of the lesions negative on 18F-DOPA and MIBG were localized with 18F-FDG PET leading the investigators to conclude that 18F-FDG was the imaging study of choice in patients with SDHB germ line mutations. In our preliminary experience, 18F-DOPA PET/CT showed high sensitivity in detecting multiple pheocromocytoma and paraganglio- ma lesions in patients with succinate dehydrogenase subunit D germ line mutation (unpublished data, an example taken from our database is shown in Fig. 8.

Zelinka et al. [72] found that for bone metastases the greatest sensitivity of 90% was with 18F-dopamine (18F- DA) PET, compared with bone scintigraphy, CT or MRI, 18F-FDG PET, and MIBG. However, in the subgroup with SDHB mutation the optimal imaging approach for bone metastases were CT and MRI (96%), bone scintigraphy (95%), and 18F-FDG PET (92%).

18F-dihydroxyphenylalanine and amine precursor positron emission tomography and positron emission tomography/computed tomography

18F-DOPA PET/CT is a promising imaging modality for chromaffin NET, with high sensitivity between 84 and 100% and high specificity between 88 and 100% [74,75,81,89]. An example from our database is shown in Fig. 9. Fottner et al. [77] investigated 30 patients with chromaffin NET including 15 with hereditary pheochro- mocytoma/PGL. They found that 18F-DOPA PET had excellent sensitivity of 98% (62/64 lesions) and specificity of 100%, compared with MIBG sensitivity of only 53% (34/64 lesions) and specificity of 91%. In another comparative study of 48 patients with catecholamine excess, 18F-DOPA PET had superior sensitivity of 90% compared with MIBG (65%), CT, and MRI (67%) [75].

Numerous studies have reported on the use of 18F-DA PET for imaging pheochromocytoma/PGL with excellent sensitivity that ranges from 90 to 100% and high specificity from 75 to 90% [78-81]. In a large study of 99 patients with suspected pheochromocytoma, 18F-DA had similar sensitivity for nonmetastatic pheochromocy- toma in comparison with MIBG, with greater sensitivity for metastatic pheochromocytoma. The use of 11C- hydroxyephedrine PET/CT for imaging pheochromocy- toma/PGL has been reported [90-93].

68 Ga-DOTA peptide positron emission tomography

Feasibility of 68Ga-DOTANOC PET imaging of pheo- chromocytoma has been reported in a single case and in a small series of five patients [82,83]. 68Ga-DOTANOC can successfully image metastatic pheochromocytoma in MIBG-negative patients, allowing consideration of 90Y- labeled peptide therapy. More recently, our group has shown, in a limited number of patients that 68Ga- DOTATATE is more sensitive than 123I-MIBG in 11 patients with chromaffin NET tumors [94]. 68Ga- DOTATATE was particularly sensitive in patients with SDHB-positive status.

Imaging of medullary thyroid cancer

MTC is a rare tumor derived from parafollicular cells (C cells) of the thyroid gland, which originate from the neural crest. These neuroendocrine tumors secrete calcitonin and carcinoembryonic antigen among other polypeptides. MTC comprise between 3 and 12% of all thyroid cancers and may be sporadic in 70-80% of patients or inherited in 20-30% [95]. Inherited MTC occurs with MEN type 2A and 2B, or due to an isolated familial syndrome, often associated with germ line mutations of the RET proto-oncogene.

18F-fluorodeoxyglucose positron emission tomography/computed tomography

There have been a number of reports in the literature of 18F-FDG PET and PET/CT being used for restaging

Fig. 7

(a)

(c)

-

(b)

(d)

18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) study in an 89-year-old man with a history of right adrenal mass and biochemical evidence of phaeochromocytoma. Axial PET and fused PET/CT (a and b), and coronal (c and d) images demonstrate a 2 cm right adrenal lesion (arrows) with maximum standardized uptake value (SUV) of 3.2 compared with the liver background SUV mean of 2.1, with a lesion/liver SUV max ratio of 1.3.

of MTC to detect recurrence [48,96-108]. Reported sensitivity using patient-based analysis ranges between 47 and 79%, with higher sensitivity between 76 and 96% found for lesion detection. These data suggest that, although 18F-FDG PET has limited sensitivity for detection of recurrence, a patient with a negative 18F- FDG PET scan is unlikely to have disease found by any other imaging modality. Specificity of 18F-FDG PET in MTC is high with few false-positive cases reported.

In a large multicenter trial of 85 patients with 55 histologically confirmed lesions, 18F-FDG PET had lesion sensitivity of 78% and specificity of 79%, performing better than most other modalities [99]. However, subsequent studies in larger numbers found 18F-FDG PET had limited sensitivity of 50%, compared with combined ultrasonography/CT/MRI imaging (87%) [98]. 18F-FDG PET has the best performance for detection of neck, supraclavicular, and mediastinal nodal disease

identifying 240 foci compared with only 74 for CT and 79 with MRI. However, CT performed better for detection of liver and lung metastases [108]. These findings have been confirmed in a similar study [105]. An example from our database is shown in Fig. 10.

Ong et al. [104] in 28 patients with recurrent MTC found an overall sensitivity of 62%; however, the sensitivity increased to 78% for calcitonin levels of more than 1000 pg/ml. Conversely, all patients with calcitonin of less than 500 pg/ml had negative 18F-FDG PET suggesting microscopic metastases or low disease burden.

18F-dihydroxyphenylalanine positron emission tomography/computed tomography

The limited sensitivity of 18F-FDG PET for imaging MTC led investigators to evaluate non-FDG PET alternatives, with 18F-DOPA PET/CT being particularly

Fig. 8

(a)

,

27

20

20

30

?

32

33

34

35

m

37

(b)

R

L

A

P

R

I

(a and b) 18F-dihydroxyphenylalanine (DOPA) positron emission tomography (PET) in a 56-year-old male succinate dehydrogenase subunit D patient with multiple parasympathetic paragangliomas in the neck, mediastinum, and abdomen. (a) Coronal whole-body images showing right neck, mediastinal paragangliomas, and right adrenal phaeochromocytoma. (b) Fusion PET/CT images of the neck (from the right to the left: coronal, sagittal, axial image) showing two sympathetic paragangliomas, which display intense 18F-DOPA uptake.

J

R

1

2

1

R

Z

18F-dihydroxyphenylalanine (DOPA) positron emission tomography/computed tomography (PET/CT) of a solitary left phaeochromocytoma. Left, coronal CT image; mid left, coronal PET image; mid right, coronal fusion PET/CT image; right, maximum intensity projection image.

Fig. 10

(a)

(b)

(d)

(c)

e

18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) for staging of medullary thyroid cancer. Maximum intensity projection image (a), corresponding axial (b and c), and coronal PET and fused PET/CT (d and e) show prominent right paratracheal lymph nodes with an increased FDG uptake (arrows) compatible with recurrent medullary thyroid nodal metastases.

promising [89,109-112]. An example from our database is shown in Fig. 11. Hoegerle et al. [111] first showed that 18F-DOPA PET had a sensitivity of 63% (17/27 foci) that was superior to 18F-FDG PET sensitivity of 44% and SRS

of 52% in staging patients with MTC, particularly in nodal disease. Superior performance of 18F-DOPA PET compared with 18F-FDG PET has been confirmed by others [109-112], whereas similar diagnostic performance

Fig. 11

R

1

2

1

PET Transaxials

R

L

18F-dihydroxyphenylalanine (DOPA) positron emission tomography/computed tomography (PET/CT) of a pretracheal relapse of medullary thyroid cancer. Bottom left, axial fusion PET/CT image; down right, maximum intensity projection image; top left, axial CT image; and top right, axial PET image.

was reported by Beuthien-Baumann et al. [110] with 18F- DOPA and 18F-FDG PET in detecting MTC recurrence, both having sensitivities of 46% in 15 patients. Therefore, 18F-DOPA PET/CT has superior sensitivity (between 47 and 83%) to 18F-FDG PET/CT for detection of disease recurrence, although neither modality can identify all sites of disease, with 18F-FDG likely having an advantage for aggressive MTC as indicated by high calcitonin levels or short calcitonin doubling times.

68Ga-DOTA peptide positron emission tomography/ computed tomography

Conry et al. [86] found that 68Ga-DOTATATE PET/CT detected MTC recurrence in 13 of 18 patients (sensitivity 72%) compared with 18F-FDG PET/CT positivity in 14 of 18 patients (sensitivity 78%). 68Ga-DOTATATE detected 23 foci compared with 28 foci with 18F-FDG. However, 10 patients had a discordant distribution of disease. Cur- rently, the role of 68Ga-DOTATATE PET/CT for the detection of recurrent MTC is uncertain as this group of NETs has variable SSTR expression [68]. Positivity with 68Ga-DOTATATE PET could allow targeted somatostatin analog therapy with 9ºY-labeled and 177 Lu-labeled radio- pharmaceuticals.

Summary

Characterization of adrenal lesions represents a diagnostic dilemma. 18F-FDG PET/CT has proven to differentiate benign from malignant lesions and may play a role in selecting patients for surgical versus conservative man- agement. Furthermore, new PET tracers are increasingly used in clinical practice for imaging sympathomedullary adrenal tumors with excellent preliminary results.

Newer positron-emitting radiotracers, which take advan- tage of specific and nonspecific metabolic pathways and molecular targets, are emerging as promising agents for the evaluation of NETs. Although 18F-FDG PET/CT remains useful for prognostication of biologically aggres- sive, dedifferentiated NETs, newer radiotracers such as 18F-DOPA and 68Ga-DOTA peptides allow sensitive and highly specific imaging of well-differentiated NETs. Selection of the most appropriate PET radiotracer for imaging may depend on an individual’s tumor grade, proliferation indices, and tumor markers.

Acknowledgements

Conflicts of interest

There are no conflicts of interest.

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