Eur J Nucl Med Mol Imaging DOI 10.1007/s00259-014-2892-6

ORIGINAL ARTICLE

68

Ga-DOTATOC PET/CT provides accurate tumour extent in patients with extraadrenal paraganglioma compared to 123I-MIBG SPECT/CT

Alexander Kroiss & Barry Lynn Shulkin & Christian Uprimny & Andreas Frech & Rudolf Wolfgang Gasser & Christoph Url & Kurt Gautsch & Ruth Madleitner & Bernhard Nilica & Georg Mathias Sprinzl & Guenther Gastl & Gustav Fraedrich & Irene Johanna Virgolini

Received: 15 June 2014 / Accepted: 4 August 2014 # Springer-Verlag Berlin Heidelberg 2014

Abstract Purpose The aim of this study was to compare the accuracy of 123I-MIBG SPECT/CT with that of 68GaDOTATOC PET/CT for staging extraadrenal paragangliomas (PGL) using both functional and anatomical images (i.e. combined cross-sectional imaging) as the reference standards. A. Kroiss (*) : C. Uprimny : R. Madleitner : B. Nilica : I. J. Virgolini Department of Nuclear Medicine, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria e-mail: [email protected] B. L. Shulkin Department of Radiological Sciences, St. Jude Children’s Research Hospital, Memphis, TN, USA A. Frech : G. Fraedrich Department of Vascular Surgery, Innsbruck Medical University, Innsbruck, Austria R. W. Gasser Department of Internal Medicine I, Innsbruck Medical University, Innsbruck, Austria C. Url Department of Otorhinolaryngology, Innsbruck Medical University, Innsbruck, Austria K. Gautsch Department of Radiology, Innsbruck Medical University, Innsbruck, Austria G. M. Sprinzl Department of Otorhinolaryngology, State Clinic, St. Poelten, Austria G. Gastl Department of Internal Medicine V, Innsbruck Medical University, Innsbruck, Austria

Methods The study included three men and seven women (age range 26 to 73 years) with anatomical and/or histologically proven disease. Three patients had either metastatic head and neck PGL (HNPGL) or multifocal extraadrenal PGL, and seven patients had nonmetastatic extraadrenal disease. Comparative evaluation included morphological imaging with CT, functional imaging with 68Ga-DOTATOC PET, and 123I-MIBG imaging. The imaging results were analysed on a per-patient and on a per-lesion basis. Results On a per-patient basis, the detection rate of 68 Ga-DOTATOC PET was 100 %, whereas that of planar 123I-MIBG imaging was 10.0 % and with SPECT/ CT 20.0 % for both nonmetastatic and metastatic/ multifocal extraadrenal PGL. On a per-lesion basis, the overall sensitivity of 68Ga-DOTATOC PET was 100 % (McNemar p<0.5), that of planar 123I-MIBG imaging was 3.4 % (McNemar p<0.001) and that of SPECT/ CT was 6.9 % (McNemar p < 0.001). Both 68 GaDOTATOC PET and anatomical imaging identified 27 lesions. Planar 123I-MIBG imaging identified only one lesion, and SPECT/CT two lesions. Two additional lesions were detected by 68Ga-DOTATOC PET but not by either 123IMIBG or CT imaging. Conclusion Our analysis in this patient cohort indicated that 68Ga-DOTATOC PET/CT is superior to 123I-MIBG SPECT/CT, particularly in head and neck and bone lesions, and provides valuable information for staging extraadrenal PGL, particularly in patients with surgically inoperable tumours or multifocal/malignant disease.

Keywords 68Ga-DOTA-TOC . PET/CT . 123I-MIBG . SPECT/CT . Extraadrenal paraganglioma

Eur J Nucl Med Mol Imaging

Introduction Neuroendocrine tumours (NET) are referred to as phaeochromocytomas when arising from the chromaffin cells of the adrenal medulla, whereas extraadrenal tumours are known as paragangliomas (PGL) [1]. Because of their neuroendocrine origin, most abdominal and thoracic extraadrenal PGL produce catecholamines and related substances, whereas head and neck PGL (HNPGL) usually do not produce such substances [1]. Although morphological imaging, such as CT, provides excellent anatomical detail and sensitivity [2], it may be difficult to distinguish between tumours derived from the sympathetic nervous system and other tumour entities when using only this modality [1]. 123I-Labelled metaiodobenzylguanidine (123I-MIBG) and 111In-pentetreotide are functional imaging markers with moderate sensitivity in localizing nonmetastatic extraadrenal PGL [1, 3–5]. Unlike MIBG, radiolabelled somatostatin (SST) analogues such as octreotide and pentetreotide are not specific for PGL, but offer high sensitivity due to SST binding, particularly in receptor subtypes 2, 3 and 5 [3]. However, both functional imaging markers are of limited use in detecting metastatic and multifocal extraadrenal PGL because of the limited resolution of planar scintigraphy and single-photon emission computed tomography (SPECT) [4–6]. Compared to planar scintigraphy and CT, PET with the 68Galabelled octreotide derivative 1,4,7,10-tetraazacyclododecaneN,N′,N′′,N′′′-tetraacetic-acid-D-Phe1-Tyr3-octreotide (68GaDOTATOC) is more sensitive and specific in NET [7], reflecting these tumours’ widespread expression of SST, particularly receptors of subtypes 2, 3 and 5 [3]. The introduction of PET combined with CT (PET/CT) into clinical practice and the development of new PET radiopharmaceuticals have produced promising results in the detection of NETs, enabling higher spatial resolution than that available with conventional scintigraphy and resulting in superior image quality and higher sensitivity in small lesions [8]. The aim of this study was to compare the accuracy of 123I-MIBG SPECT/CT with that of 68Ga-DOTATOC PET for staging extraadrenal PGL, using both functional and anatomical images (i.e. combined cross-sectional imaging) as the reference standards.

Materials and methods Patients This retrospective study included ten patients with suspected or histologically proven extraadrenal PGL who had been referred to our institution at Innsbruck Medical University for initial disease staging or restaging between March 2011 and August 2012 (three men and seven women, age at

diagnosis 26 to 73 years; Table 1). Seven patients had nonmetastatic HNPGL (two men and five women, age range 26 to 73 years), with bilateral disease seen in two patients (patients 2 and 9). Three patients (one man and two women, age range 49 to 60 years) had malignant HNPGL with either bone metastases (patients 2 and 10) or multifocal extraadrenal disease (patient 7). Malignancy was defined as the presence of tumour deposits in regions where chromaffin cells are normally absent (i.e. liver, lung, bone) [8], with diagnostic CT images used as the reference standard [9]. HNPGL surgery had previously been performed in three of the women, all of whom experienced disease relapse (patients 2, 3 and 10). The average time between surgery and imaging studies was 16.7 years (range 6.0 to 34.0 years); this long interval was due to relapse of disease even after several months or years. Imaging was performed to evaluate the eligibility for 131IMIBG therapy of patients with surgically inoperable extraadrenal manifestations (e.g. in the head and neck, abdomen or bone) previously verified by sonography and/or MRI. Patients with low or missing 123I-MIBG uptake underwent 68 Ga-DOTATOC PET/CT staging both to evaluate their eligibility for peptide receptor radionuclide therapy (PRRT) and to fully delineate the extent of tumour disease. Imaging procedures were performed within an average time of 50.0 days. During this period, no therapy or intervention was performed. Because of stable disease over years in patients with anatomically or histologically proven PGL, none of these patients received long-acting SST analogues before 68Ga-DOTATOC PET/CT staging. Patients did not undergo genetic analysis (e.g. for succinate dehydrogenase subunit B) before imaging. This retrospective study was performed according to the principles of the Declaration of Helsinki and its subsequent amendments [10]. Written informed consent was obtained from all patients before the start of the study, and all studies were performed in the course of the standard clinical and diagnostic work-up. 123

I-MIBG planar and SPECT/CT imaging

Patients were imaged after intravenous administration of 123IMIBG, according to the procedure guidelines of the EANM [11]. To block thyroid uptake, patients received a saturated solution of potassium iodine three times daily on four consecutive days, starting the day before 123I-MIBG administration. Medications known to interfere with 123I-MIBG uptake were discontinued, such as tricyclic antidepressants or sympathomimetic amines [11]. Planar scintigraphy Whole-body imaging was obtained on a hybrid SPECT/CT scanner with a built-in flat-panel CT system (BrightView XCT; Philips Healthcare, Best, Netherlands) 24 h after injection of a

Eur J Nucl Med Mol Imaging Table 1 Patient characteristics Patient no.

Sex

Age (years)

Confirmation

Tumour location

Metastases

Chromogranin A (U/L)a

Neuron-specific enolase (μg/L)b

1 2 3 4

Male Female Female Female

43 31 49 67

CT CT/histology CT/histology CT

Head and neck Head and neck Head and neck Head and neck

None None Bone None

18.4 14.8 13.7 n.a.

28.8 18.2 14.7 n.a.

5 6 7 8 9 10

Male Female Male Female Female Female

26 68 58 73 65 60

CT CT CT CT CT CT/histology

Head and neck Head and neck Head and neck Abdomen, larynx head and neck Head and neck Head and neck

None None None None None Bone

n.a. n.a. 32.4 12.4 19.7 n.a.

n.a. n.a. 14.5 19.7 22.3 n.a.

n.a. not available a

Normal range 2.0 – 18.0 U/L

b

Normal range 0.0 – 16.3 μg/L

mean activity of 401 MBq (range 395 – 420 MBq) [11]. The scan speed for whole-body imaging was 12 cm/min. The camera was equipped with a low-energy, high-resolution, parallel-hole collimator. For whole-body imaging, the following parameters were used: matrix size 1,024×1,024, energy window at 159 keV with 15 % width, 180° detector head configuration.

SPECT/CT Directly after planar imaging, late-phase SPECT/CT images of the head and neck (ten patients), thorax (two patients) and abdomen (one patient) were acquired. The following parameters were used for CT acquisition: slice thickness 1 mm, 20 mA, 120 kV. The following parameters were used for SPECT acquisition: 80 projections, 128×128 matrix, energy window at 159 keV with 15 % width, 20 s acquisition time per projection. For iterative reconstruction of the SPECT data, four iterations and 16 subsets were used with a Hanning filter and a cut-off of 1.2. Attenuation correction was performed using the CT data and the resolution recovery method Astonish (Philips). SPECT and CT images were transferred to a workstation and automatically fused using dedicated software (Extended Brilliance Workspace; Philips Healthcare, Best, Netherlands). A software-based, retrospective image fusion of 123I-MIBG SPECT/CT and diagnostic CT images from PET/CT was performed by General Electrics (GE, PETVCAR, Advanced Workstation 4.5) to assist in distinguishing pathological from physiological MIBG uptake. The average time between conventional scintigraphy and PET imaging studies was 50.0 days (range 6 – 140 days).

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Ga-DOTATOC PET/CT

68

Ga-DOTATOC was prepared using a fully automated synthesis method, as previously described [12]. 68Ga-DOTATOC PET/CT imaging was performed using a dedicated PET/CT system (Discovery 690; GE Healthcare, Milwaukee, WI). A low-dose CT scan was performed for attenuation correction of the PET emission data. CT acquisition parameters for the lowdose and “GE smart mA dose modulation” protocols were 100 kV and 50 mA, respectively. The helical thickness was 3.75 mm, and the spiral pitch factor was 1.375, with a rotation time of 0.8 s. Attenuation-corrected whole-body scans (skull base to upper thighs) were acquired in three-dimensional mode (emission time 2 min per bed position). Depending on the patient’s body length, six or seven bed positions were used, with an axial field-of-view of 15.6 cm per bed position. For iterative reconstruction of the time-of-flight data, two iterations and 32 subsets were used with a filter cut-off of 6.4 mm. Patients received an intravenous 68Ga-DOTATOC dose of 122.2±12.7 MBq (mean±SD), and image acquisition was started 60 min after injection. All patients received contrastenhanced whole-body 68 Ga-DOTATOC PET/CT and underwent a helical CT scan on a 64-slice CT scanner with a slice thickness of 3.75 mm and a display field-of-view of 50 cm, starting from the base of the skull and continuing to the upper thighs. During image acquisition, a bolus of ionized contrast agent (Iomeron 400 mg/mL) was injected into the antecubital vein. The bolus was administered at a rate of 3.5 mL/s, followed by a late arterial phase after 40 s and a portal phase after 70 s. Depending on the patient’s body weight, 60 mL to 120 mL of the contrast agent was administered. CT acquisition parameters for the diagnostic and “GE

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smart mA dose modulation” protocols were 100 – 120 kVand 120 mA, respectively, with the actual dose determined by the patient’s body weight. The helical thickness was 3.75 mm, and the spiral pitch factor was 0.984, with a rotation time of 0.8 s.

Image interpretation A positive diagnosis of PGL or tumour metastases was based on the specific appearance of malignant disease on CT images as reported elsewhere [8]. Diagnostic CT images were interpreted by an experienced radiologist who was aware of the clinical data but unaware of the scintigraphic results. 68GaDOTATOC PET/CT and 123I-MIBG planar images (including SPECT/CT images) were interpreted independently by two experienced nuclear medicine physicians, who were aware of the patient’s clinical history but unaware of the results of anatomic imaging. In the event of discordant results the disagreement was resolved by consensus. The criteria for determining a scintigraphic lesion to be PGL were clear demarcation of the lesion, tracer accumulation higher than that of the liver, and tracer uptake higher than physiological activity [8]. 123 I-MIBG uptake in the adrenal glands was considered to be normal if it was mild and symmetrical and the glands were not enlarged [9]. PET findings were compared only visually without calculation of the maximum standardized uptake values. Per-lesion and per-patient analyses were performed for all imaging modalities. For per-patient analyses, scans were considered positive if at least one malignant lesion (primary tumour or metastases) was seen, regardless of the number of foci. Because histological proof of metastatic lesions was unavailable in most patients, findings on combined cross-sectional imaging studies were used as the reference standards [6, 8, 13]. For calculation of detection rates, studies were considered to be either positive or negative, with combined cross-sectional imaging being the gold standard because functional imaging is only complementary to anatomical imaging [13].

Table 2 Imaging modalities by lesion

Combined cross-sectional imaging was the reference standard for evaluation of detection rates of functional imaging modalities

For lesion-based analyses, we defined two groups of patients on the basis of their CT findings: The first group consisted of those with nonmetastatic extraadrenal PGL originating from the head and neck, and the second group consisted of those with metastatic or multifocal extraadrenal PGL (Table 2). Although no validated histological criteria for malignancy currently exist [14], we combined patients with multifocal and metastatic disease into one group because the patient with multifocal PGL (patient 7) also had lesions with nonphysiological tracer uptake (i.e. abdominal soft tissue), which are often associated with higher malignant potential [1]. A separate analysis on a per-lesion basis was performed on the following areas: head and neck, thorax, abdomen (including soft tissue), and bone (Table 3).

Assessment of laboratory parameters Levels of both chromogranin A and neuron-specific enolase were elevated in two patients (Table 1). Additionally, three of the six patients in whom chromogranin A measurements were available had high expression of tumour markers. Furthermore, four of the six patients in whom neuron-specific enolase values were available had high expression of tumour markers.

Statistical analyses Statistical analyses were performed using dedicated statistical software (SPSS v. 15). The detection rate of functional imaging was assessed on a per-patient and on a perlesion basis using the McNemar test. Combined crosssectional imaging was used as the reference standard for evaluation of the detection rate of functional imaging modalities. Nonparametric methods were used to compare anatomical imaging. All p values less than 0.05 were considered to be statistically significant.

Type of lesion

Modality

No. of positive lesions

No. of positive lesions on CT

Detection rate of modality (%)

Nonmetastatic PGL

68

Ga-DOTATOC Planar 123I-MIBG 123 I-MIBG SPECT/CT

11 0 1

9 9 9

100 0.0 9.1

Metastatic/multifocal PGL

68

18 1 1 29 1 2

18 18 18 27 27 27

100 5.6 5.6 100 3.4 6.9

All

Ga-DOTATOC Planar 123I-MIBG 123 I-MIBG SPECT/CT 68 Ga-DOTATOC Planar 123I-MIBG 123 I-MIBG SPECT/CT

Eur J Nucl Med Mol Imaging Table 3 Per-lesion comparison of scintigraphic imaging findings according to anatomical distribution Location

CT

68

Planar 123 I-MIBG

123

Head and neck Chest Abdomen Bone Total

15 0 2 10 27

17 0 2 10 29

0 0 1 0 1

1 0 1 0 2

Ga-DOTATOC

I-MIBG SPECT/CT

Results All 27 lesions seen on anatomical images were detected by 68 Ga-DOTATOC PET, whereas planar 123 I-MIBG and SPECT/CT imaging failed to detect 26 and 25 lesions, respectively. PGL of the adrenal gland were not apparent on

A

functional or anatomical images. On a per-patient basis, the detection rate of 68Ga-DOTATOC PET was 100 % (95 % confidence interval, 95 % CI, 72 – 100 %), whereas the detection rates of planar 123I-MIBG and SPECT/CT imaging were only 10.0 % and 20.0 %, respectively, for nonmetastatic and metastatic extraadrenal PGL (95 % CI 2 – 40 % and 6 – 51 %, respectively). On a per-lesion basis, the detection rate of 68Ga-DOTATOC PET in nonmetastatic extraadrenal PGL was 100 % and of planar 123I-MIBG and SPECT/CT imaging were 0.0 % and 9.1 %, respectively. On a per-lesion basis in patients with malignant extraadrenal disease, the detection rate of 68Ga-DOTATOC PET was 100 % (Fig. 1) and of 123I-MIBG imaging (including SPECT/CT) was 5.6 % (Table 2, Fig. 2). All head and neck lesions seen on anatomical images were verified by 68Ga-DOTATOC PET, but only one, which was negative on planar 123I-MIBG imaging, was detected by SPECT/CT (Table 3). One abdominal lesion was positive on

B

C

D

E

F

Fig. 1 Imaging in a 58-year-old man with multifocal extraadrenal disease. The maximum intensity projection (MIP) image (a) and transverse image (b, d) show intense focal 68Ga-DOTATOC uptake in the head and neck area. The diagnostic CT images (c, e) show strong contrast enhancement, consistent with HNPGLs (arrows). The intense focal uptake in the

G

abdomen (a, f) is confirmed on diagnostic CT images (g arrow) as being an extraadrenal, soft-tissue PGL lesion. The small focus of 68GaDOTATOC uptake superior to the left upper lobe of the thyroid gland (a arrow) is a PGL lesion of the larynx (confirmed by diagnostic CT)

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A

B

C

D

E

F

Fig. 2 Additional imaging in the patient seen in Fig. 1. The intense focal 123 I-MIBG uptake of the abdomen seen on planar images (a, b arrows) was confirmed by 68Ga-DOTATOC PET/CT as being a soft-tissue PGL lesion (see Fig. 1a, f, g). After software-based image fusion of SPECT images with diagnostic CT images, symmetrical physiological 123I-

MIBG uptake was observed in the parotid (c) and submandibular (e) glands. All verified head and neck lesions (d, f arrows) were 123I-MIBGnegative (c, e). 68Ga-DOTATOC PET/CT changed the tumour staging from primary tumour to multifocal disease (see Fig. 1)

all imaging modalities, whereas the other abdominal lesion was positive on 68Ga-DOTATOC PET and diagnostic CT but negative on both planar 123I-MIBG and SPECT/CT. All bone lesions detected by CT and 68Ga-DOTATOC PET (Fig. 3) were negative on both 123I-MIBG and SPECT/CT imaging (Table 3, Fig. 4). The overall detection rate of 68GaDOTATOC PET on a per-lesion basis (combining multifocal/metastatic and nonmetastatic extraadrenal PGL) was 100 % (p<0.5; 95 % CI 88 – 100 %) and that of planar 123 I-MIBG and SPECT/CT imaging was 3.4 % (p<0.001) and 6.9 % (p<0.001), respectively (95 % CI 1 – 17 % and 2 – 22 %, respectively). Comparing the functional imaging techniques, planar 123I-MIBG detected one lesion and SPECT/CT two lesions, whereas 68Ga-DOTATOC PET detected 29 lesions. Of these 29 lesions, two SST-positive lesions, which were both 123I-MIBG-negative, were not evident on CT images.

Discussion In contrast to anatomical imaging, functional imaging provides high sensitivity and specificity in detecting PGL, distinguishing between scars and tumour recurrence after previous surgery, which had been performed in three of our patients before staging. 123I-MIBG imaging has been found to be highly sensitive and specific in detecting nonmetastatic extraadrenal PGL, but less sensitive in detecting metastatic lesions [1] and nonsecreting tumours of the head and neck region [3–5], which was also observed in our study for both metastatic and nonmetastatic PGL disease. To explain this on a molecular level, it has been suggested that extraadrenal PGL could undergo dedifferentiation, leading to a loss of norepinephrine transporter or vesicular monoamine transporter (VMAT), which could then lead to false-negative findings in metastatic disease [15]. In contrast to the excellence of 123I-

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A

B

C

D

E

Fig. 3 Imaging in a 60-year-old woman with HNPGL with bone metastases. A maximum intensity projection (MIP) image (a red arrow) and transverse image (b) show intense focal 68Ga-DOTATOC uptake in the right head-and-neck area. The diagnostic CT image shows strong contrast enhancement, consistent with HNPGL (c arrow). Outside the head-andneck area, intense focal 68Ga-DOTATOC uptake is seen in multiple

regions (a MIP black arrow), all confirmed by diagnostic CT as being bone metastases of the vertebrae. For example, the transverse image shows a huge area of sclerosis in the right body of the fifth thoracic vertebra (d arrow), which was confirmed as being osteoblastic metastasis after 68Ga-DOTATOC PET/CT fusion (e)

MIBG imaging in the detection of primary sympathetic PGL, its sensitivity is low in parasympathetic HNPGL [16]. Fottner et al. suggested that this could result from the under-expression of VMAT-1 in HNPGL [17]. As shown by Ilias et al. scintigraphy with 111In-pentetreotide has a low sensitivity in the detection of primary sympathetic PGL [9]. However, it can be very useful in detecting metastatic disease [9] and parasympathetic HNPGL [13]. It has been suggested that these differences in sensitivities are related to the expression of specific SST receptor subtypes [5]. Both 111In-pentetreotide and anatomical imaging (CT/ MRI) have a sensitivity of 93 % in the detection of HNPGL, with that of 123I-MIBG imaging being only 44 %, suggesting that 111In-pentetreotide is a more suitable functional imaging tool for assessing HNPGL disease, particularly when there is high clinical suspicion and negative 123I-MIBG scintigraphy [3]. However, the main disadvantage of 111In-pentetreotide scintigraphy remains the inherently limited spatial resolution of SPECT [4].

A study comparing the accuracy of 68Ga-DOTATATE PET/ CT and 123I-MIBG SPECT imaging in phaeochromocytoma and extraadrenal PGL has shown the superiority of SST PET/ CT over conventional scintigraphy: 68Ga-DOTATATE was superior to 123I-MIBG in detecting lesions in all anatomical locations, particularly in bone [18], which is in line with our finding that 68Ga-DOTATOC PET was more sensitive in detecting metastatic phaeochromocytoma than planar 123I-MIBG imaging on a per-lesion basis [19]. Sharma et al. have recently shown a high detection rate of 68Ga-DOTANOC PET/CT in HNPGL compared to conventional imaging (CT/MRI) and 131 I-MIBG scintigraphy [20]. Previous studies by our group have confirmed the high detection rate (100 %) of 68GaDOTATOC PET/CT in nonmetastatic and metastatic extraadrenal PGL, including HNPGL, which was most pronounced in bone and abdominal lesions, compared to that of 18 F-DOPA PET/CT [21]. We found that 68Ga-DOTATOC PET/CT was better than 123I-MIBG imaging for identifying extraadrenal PGL, particularly bone metastases. Additionally, 68 Ga-DOTATOC PET/CT was superior to 123I-MIBG imaging

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Fig. 4 Additional imaging in the patient seen in Fig. 3. No pathological uptake is seen on planar 123I-MIBG images (a, b). The transverse diagnostic CT image shows strong enhancement (c arrow), which 68GaDOTATOC PET/CT confirmed as HNPGL (see Fig. 3a–c). After software-based image fusion of SPECT and diagnostic CT, symmetrical physiological 123I-MIBG uptake is observed in the submandibular glands

(d). The HNPGL of the right side is SPECT/CT-negative (red arrow d). The transverse diagnostic CT image (e arrow) shows a huge area of sclerosis in the right body of the fifth thoracic vertebra, which was negative for bone metastasis by SPECT/CT fusion (f) but verified as being bone metastasis by 68Ga-DOTATOC PET/CT (see Fig. 3d, e)

for detecting soft-tissue and head and neck lesions, indicating that 68Ga-DOTATOC may be more sensitive than 123I-MIBG, especially in detecting or excluding small metastatic lesions [1]. The fact that most lesions that were verified by 68GaDOTATOC PET and anatomical imaging were negative on both planar 123I-MIBG and SPECT/CT imaging, respectively, emphasizes the need to combine functional and anatomical imaging (PET/CT) to fully delineate the extent of tumour disease [4, 5]. Thus, combined cross-sectional imaging increased diagnostic confidence and enhanced the detection rate in two patients of our study who had additional 68 Ga-DOTATOC PET-positive lesions [8, 13, 21]. Furthermore, the 68Ga-DOTATOC PET/CT results led to a change in tumour stage assessment from primary tumour to multifocal disease (Fig. 1), in line with previous findings of Sharma et al. who also observed distant metastases in 68 Ga-DOTANOC PET/CT staging of HNPGL [20]. This small retrospective study had certain limitations. Only two patients had metastatic disease, and only one had

multifocal extraadrenal PGL. Therefore, a prospective study in a larger patient cohort is warranted to establish the true clinical value of 68Ga-DOTATOC in malignant extraadrenal PGL. Due to the high vascularization rate of extraadrenal PGL, a biopsy of suspicious foci cannot be routinely performed. Therefore, histological proof of visualized lesions, including morphological and scintigraphic imaging, was not clinically feasible. Furthermore, we were unable to calculate the specificity in the detection of nonmetastatic or metastatic/ multifocal extraadrenal PGL because of limited follow-up PET/CT results due to the retrospective study design. Conclusion The results in this small patient cohort indicate that 68GaDOTATOC PET/CT is superior to 123I-MIBG scintigraphy (including SPECT/CT) in the detection of nonmetastatic and metastatic extraadrenal PGL disease, particularly head and neck and bone lesions, respectively. 68Ga-DOTATOC PET can help in the selection of patients for PRRT if tumours are

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unresectable or metastatic. Prospective studies are required to confirm the superiority of 68Ga-DOTA-TOC PET over 123IMIBG imaging for evaluating extraadrenal PGL.

Acknowledgments We are grateful to Mathias Wochinz and Boris Warwitz (Department of Nuclear Medicine, Innsbruck Medical University) for their work on the project. We thank Dr. Claudia Goetsch (Department of Internal Medicine I, Innsbruck Medical University) and Dr. Lydia Posch (Department of Vascular Surgery, Innsbruck Medical University) for their support on this project. We also thank Harald Kühschelm for statistical advice, and Philipp Heinricher and Dr. Cherise Guess (Department of Scientific Editing, St. Jude Children’s Research Hospital) for editorial assistance. Conflicts of interest None.

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