Introduction

Pheochromocytomas are rare tumors arising from the chromaffin cells of the adrenal medulla [1]. They represent a rare (<1 %) but potentially curable cause of hypertension [2]. While the majority of pheochromocytomas are sporadic, in about a quarter of unselected cases they may be associated with hereditary syndromes like multiple endocrine neoplasia (MEN), von Hippel-Lindau syndrome (VHL), neurofibromatosis 1, and tuberous sclerosis [3]. The diagnosis of pheochromocytoma is established by measurement of blood and urinary catecholamines or their metabolites, followed by demonstration of an adrenal mass on anatomical (CT/MRI) imaging. However, biochemical markers have high sensitivity (96–100 %), but low specificity (69 %) for the detection of pheochromocytomas [4]. Similarly, the specificity of CT or MRI is also limited for differentiating pheochromocytoma from other adrenal lesions [5]. These limitations have led to reliance on functional imaging methods in order to avoid unnecessary surgery.

131/123I-Metaiodobenzylguanidine (MIBG) scintigraphy is currently the functional imaging of choice for pheochromocytoma [6], but suffers from drawbacks like limited spatial resolution, difficulty in detection of small tumors (<1.5–2.0 cm), or large tumors with extensive necrosis/hemorrhage, lack of tracer uptake in some tumors, and interference with certain medications, all of which can lead to false-negative results [7]. Addition of single photon emission computed tomography (SPECT) improves the sensitivity [8], but even then the spatial resolution is low (∼1.5 cm) and the detection of small lesions is often difficult. Given the superior resolution of positron emission tomography (PET) over SPECT, functional imaging of pheochromocytoma has been attempted with a wide array of PET tracers like 18F-fluorodeoxyglucose (FDG) [9], 18F-fluorodopa (FDOPA) [10], 18F-fluorodopamine (FDA) [11], 11C-hydroxyephedrine (HED) [12], and 68Ga-DOTA-peptides [13] with encouraging results. Expression of somatostatin receptors (SSTR) by pheochromocytomas [14] facilitates targeted PET imaging with 68Ga-DOTA-peptides (68Ga-DOTATOC, 68Ga-DOTANOC, and 68Ga-DOTATATE). However, to date very few studies have evaluated 68Ga-DOTA-peptide PET/CT (only one with 68Ga-DOTANOC) in pheochromocytomas and only in small and mixed patient populations [15–19]. Therefore, the purpose of the present study was to comprehensively evaluate the diagnostic accuracy of 68Ga-DOTANOC PET/CT in a large number of patients with suspected pheochromocytoma and compare the results with 131I-MIBG imaging when available (123I-MIBG is not available in our country).

Materials and methods

The present retrospective study was approved by the Institutional Ethics Committee and because of the retrospective nature written informed consent was waived. The inclusion criteria were clinical and/or biochemical suspicion of pheochromocytoma along with adrenal abnormality on contrast CT. The biochemical suspicion was based on the presence of one or more of the following: urinary epinephrine (>20 μg/day), urinary norepinephrine (>90 μg/day), urinary vanillylmandelic acid (>7.9 mg/day), urinary total metanephrine (>1.2 mg/day), plasma epinephrine (>85 pg/ml), plasma norepinephrine (500 pg/ml), plasma metanephrine (>400 pg/ml), plasma normetanephrine (>676 pg/ml), and plasma methoxytyramine (>1,800 pg/ml). A total of 62 patients who underwent 68Ga-DOTANOC PET/CT between March 2007 and December 2012 satisfied the inclusion criteria. Data of these 62 patients were retrieved from departmental registries and analyzed. In addition, 40 of these 62 patients also had undergone 131I-MIBG scintigraphy. Of these 62 patients, 10 had been previously included in the pilot study by Naswa et al. [18].

68Ga-DOTANOC synthesis

68Ga-DOTANOC synthesis was carried out using the method previously detailed by Zhernosekov et al. [20] and is briefly described here: 30–50 mCi 68Ge/68Ga generator (Cyclotron Co Ltd., Obninsk, Russia) was eluted using 0.1 M hydrochloric acid (HCl). The eluent was loaded on a miniaturized column of organic cation-exchange resin to pre-concentrate and pre-purify (using 80 % acetone/0.15 M HCl). The processed 68Ga was directly eluted with 97.7 % acetone/0.05 M HCl into the reaction vial containing 30–50 μg of DOTANOC. Synthesis was carried out at approximately 126 °C for 10–15 min. This was followed by removal of labeled peptide from unlabeled peptide using a reverse-phase C-18 column, using 400 μl of ethanol. This was further diluted with normal saline and passed through a 0.22-μm filter to obtain a sterile preparation for injection. A labeling yield of >95 % and specific activity (>15 GBq/μmol) were achieved after 10–15 min of heating.

68Ga-DOTANOC PET/CT imaging

Fasting was not required. A dose of 132–222 MBq (4–6 mCi) of 68Ga-DOTANOC was injected intravenously. After a 45- to 60-min uptake period PET/CT acquisition was started on a dedicated PET/CT scanner (Biograph 2, Siemens Medical Solutions, Erlangen, Germany). First, CT acquisition was performed on a spiral dual-slice CT with a slice thickness of 4 mm, pitch of 1, a matrix of 512×512 pixels, and pixel size of 1 mm. No oral or intravenous contrast was used in CT. After CT acquisition, 3-D PET acquisition of the same axial range was done from the base of the skull (including pituitary fossa) to mid thighs, using a matrix of 128×128 pixels and slice thickness of 1.5 mm. CT-based attenuation correction of the emission images was then applied. The PET images were reconstructed by iterative method ordered subset expectation maximization (OSEM) with two iterations and eight subsets. The reconstructed attenuation-corrected PET images, CT images, and fused images of matching pairs of PET and CT images were then available for review in axial, coronal, and sagittal planes, as well as in maximum intensity projections (MIP), 3-D cine mode.

131I-MIBG imaging

In 40 patients 131I-MIBG scintigraphy with/without SPECT/CT was done within ±2 weeks of PET/CT. None of the patients had received any drugs that would interfere with MIBG uptake, such as tricyclic antidepressants or sympathomimetic amines. Following the intravenous injection of a mean dose of 37 ± 12 MBq of 131I-MIBG (GE Healthcare, Braunschweig, Germany), a planar scintigraphy image was obtained with a large field of view dual-head gamma camera (Symbia E, Siemens Medical Solutions, Hoffman Estates, IL, USA) and a high energy-collimator. Whole-body images in the ventral and dorsal planes as well as target images of the abdomen were acquired 48 h after injection. In 20 patients, additional SPECT/CT of the adrenals was also performed. SPECT was done with the following parameters: 128×128 matrix, 120 projections in 3° angle increments, and an acquisition time of 40 s per projection. SPECT was followed by CT examination with acquisition parameters of 130 kV, 100 mAs, pitch of 1, and 512×512 matrix using standard filters. All SPECT/CT images were uniformly processed with commercially available e.soft software (Siemens Medical Solutions, Knoxville, TN, USA) on a Syngo nuclear medicine workstation (Siemens Medical Solutions, Hoffman Estates, IL, USA).

Image analysis

68Ga-DOTANOC PET/CT studies were evaluated by two experienced nuclear medicine physicians. To provide a “clean” analysis of PET/CT results they were blinded to the patient’s clinical, biochemical, and previous imaging findings. Their findings were concordant for 60 of the 62 patients. For the remaining two patients a consensus diagnosis was reached after discussion. For qualitative evaluation of PET/CT images the presence of an adrenal lesion (nodule/mass) on CT showing visual 68Ga-DOTANOC uptake was taken as positive for pheochromocytoma. Care was taken not to confuse the physiological uptake in the adrenal gland for tumor uptake. In the absence of a definite adrenal lesion on PET/CT, asymmetrically increased 68Ga-DOTANOC uptake in an adrenal was taken as positive. Any other nonphysiological focal area of increased 68Ga-DOTANOC uptake was looked for and was classified as a second primary or metastasis. For the purpose of quantitative analysis the maximum standardized uptake values (SUVmax) and average SUV (SUVmean) were measured for all adrenal lesions, normal liver, and the unaffected adrenal (if present). The SUVmean and SUVmax were measured by drawing an isocontour to delineate 50 % of the highest radioactivity concentration as a 50 % cutoff region of interest (ROI). If a primary tumor was not found, the highest SUV in the adrenal glands was recorded. A large circular ROI was drawn in the posterior part of the right liver lobe, and the SUVmean of the liver (SUVliver) was recorded. SUVmax was also recorded for the second primary or metastatic lesions, if present. All SUV calculation was done via the default method by body weight [SUV = mean ROI activity (MBq/g)/injected dose (MBq)/body weight (g)].

131I-MIBG images were evaluated by two experienced nuclear medicine physicians independently, blinded to clinical, biochemical, and other imaging findings. Any focal accumulation of 131I-MIBG in the adrenal glands or extra-adrenal regions that exceeded the normal regional tracer uptake was considered abnormal. They were in agreement for 37 of 40 patients. For the remaining three patients a consensus was reached after discussion.

Reference standard

Histopathology was used as reference standard for 52 lesions (48 pheochromocytomas, 3 adenomas, and 1 adrenocortical carcinoma). For the remaining 18 lesions, a combination of clinical, biochemical, and imaging follow-up of at least 6 months was used as reference standard (2 pheochromocytomas and 16 adenomas/normal adrenals) as tumor biopsy is contraindicated in these groups of neoplasms. The median duration of follow-up was 9 months (range 6–36 months). Based on these above-mentioned reference standards, 50/70 (71.4 %) lesions were proven to be pheochromocytoma. The diagnosis of malignant pheochromocytoma was considered if there was clear documentation of metastasis on histopathology and/or imaging. Medullary thyroid carcinoma (MTC) in all five patients (four thyroidal and one nodal) was histologically/cytologically confirmed.

Statistical analysis

All statistical analysis was done using MedCalc 11.3.0.0 (MedCalc Software, Acacialaan, Ostend, Belgium). The Kolmogorov-Smirnov test was used to check the normality of the data. The Wilcoxon rank sum test was used to compare paired data and Mann-Whitney U test for unpaired data. Spearman’s correlation coefficient analysis was used to test the association of two variables. Receiver-operating characteristic curve (ROC) analysis was done to derive cutoff levels for SUV parameters. McNemar’s test was used to compare the diagnostic accuracy of 68Ga-DOTANOC PET/CT with 131I-MIBG scintigraphy. A p value < 0.05 was considered significant.

Results

Patient characteristics

Patient characteristics are detailed in Table 1. In 30 patients only one of the biochemical markers detailed in the “Materials and methods” section was elevated. In the remaining 32 patients, variable combination of these markers was elevated. As different biochemical markers were available for different patients, these are not detailed.

Table 1 Patient characteristics
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68Ga-DOTANOC PET/CT diagnostic accuracy

Patient-based analysis

68Ga-DOTANOC PET/CT was interpreted as positive for pheochromocytoma in 41/62 (66.1 %) and negative in 21/62 (33.9 %) patients. On a patient-based analysis it was true-positive (TP) in 38, true-negative (TN) in 17, false-positive (FP) in 3, and false-negative (FN) in 4 patients (Table 2).

Table 2 Diagnostic accuracy of 68Ga-DOTANOC PET/CT for pheochromocytoma on patient wise and lesion wise analysis (results with 95 % confidence interval)
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Lesion-based analysis

Of the total 70 lesions seen on CT, 68Ga-DOTANOC PET/CT was interpreted as positive for pheochromocytoma in 49/70 (70 %) and negative in 21/70 (30 %). On a lesion-based analysis it was TP in 46, TN in 17, FP in 3, and FN in 4 patients (Table 2). All three FP lesions on PET/CT were found to be adenoma at histopathology. In three of the four FN lesions, no mass/nodule was seen on the non-contrast CT part of PET/CT. While one patient had a definite nodule (1.1 cm), the remaining three showed only asymmetrical thickening.

MEN2 syndrome

Among 14 patients with MEN2, 68Ga-DOTANOC PET/CT was positive for pheochromocytoma in 9 and negative in 5. In these patients with 18 suspicious adrenal lesions on CT, PET/CT was TP for 13 and TN for 5 lesions. There were no FP or FN lesions (accuracy 100 %). In addition, 68Ga-DOTANOC PET/CT also demonstrated MTC in four patients (two primary and two recurrent) and nodal metastasis from MTC in one patient.

Malignant pheochromocytoma

68Ga-DOTANOC PET/CT was positive for pheochromocytoma in all seven patients with malignant pheochromocytoma (nine lesions, accuracy 100 %). In all these seven patients 68Ga-DOTANOC PET/CT also demonstrated metastases. The metastatic sites were node in six patients, bone in three, liver in three, and lung in one. In three patients there was more than one site of metastasis. In one patient, 68Ga-DOTANOC PET/CT also demonstrated a synchronous thoracic paraganglioma.

Semiquantitative analysis

Overall

The details of various SUV parameters are presented in Table 3. Size and all SUV parameters were significantly higher for pheochromocytoma than that for other adrenal lesions (Table 4 and Fig. 1). Unpaired and paired analyses were performed to compare the SUV parameters in tumors and normal adrenal glands. At unpaired analysis comparing tumors with all normal glands, the SUVmax but not SUVmean of the adrenal tumors was significantly higher (Table 4). For paired analysis patients with bilateral tumors and unilateral adrenals were excluded, and tumor SUV parameters were compared with contralateral normal adrenal. On paired analysis both SUVmax and SUVmean of adrenal tumors was significantly higher (Table 4). On ROC analysis (Table 5) a significant cutoff could be derived for all SUV parameters. Among these parameters, a tumor SUVmax/SUVliver cutoff of >2.5 showed the highest diagnostic accuracy (AUC 0.741, 95 % confidence interval 0.622–0.838).

Table 3 Results of semiquantitative analysis of 68Ga-DOTANOC PET/CT
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Table 4 Comparison of size and SUV parameters between subgroups
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Fig. 1
figure 1

Box and whisker plots comparing the SUV parameters between non-pheochromocytoma adrenal lesions (solid boxes) and pheochromocytoma (dashed boxes). The circles represent the outliers

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Table 5 Results of ROC analysis
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MEN2 syndrome

Comparison of size and SUV parameters of the tumors among patients with and without MEN2 is detailed in Table 4. While the SUVmax and SUVmean of tumors were significantly higher in patients with MEN2, no difference was noted for other parameters.

Malignant pheochromocytoma

The comparison of size and SUV parameters of the tumors among patients with benign and malignant pheochromocytoma is detailed in Table 4. No significant difference was found between benign and malignant pheochromocytoma for any of these parameters.

Correlation with tumor size

The mean tumor size was 4.1 ± 2.4 cm (median 3.8, range 0.6–11). We assessed the relationship between lesion size and the respective SUV parameters to see whether tumor size correlated with SSTR expression. No significant correlation was noted between tumor size and tumor SUVmax (ρ = 0.227, p = 0.099), tumor SUVmean (ρ = 0.155, p = 0.262), tumor SUVmax/SUVliver (ρ = 0.131, p = 0.347), and tumor SUVmean/SUVliver (ρ = 0.092, p = 0.510).

Comparison with 131I-MIBG imaging

Overall

Both68Ga-DOTANOC PET/CT and 131I-MIBG imaging were available for 45 adrenal lesions in 40 patients (Figs. 2–5). The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of both imaging methods for these 45 lesions are detailed in Table 6. On a lesion-based comparison 68Ga-DOTANOC PET/CT was superior to 131I-MIBG imaging for pheochromocytoma (p = 0.035). Results of 68Ga-DOTANOC PET/CT and 131I-MIBG imaging were discordant for 15/45 (33.3 %) lesions.

Fig. 2
figure 2

A 37-year-old man with headache, paroxysmal hypertension, elevated 24-h urinary metanephrine, and left adrenal mass on CT. MIP 68Ga-DOTANOC PET image (a) shows abnormal radiotracer uptake in the left suprarenal region (arrow), corresponding to the necrotic left adrenal mass on PET/CT image (c, arrow). Anterior 131I-MIBG scintigraphy image (b) is normal and on SPECT/CT image no 131I-MIBG uptake is seen in the adrenal mass (arrow). The patient underwent surgery and the diagnosis of pheochromocytoma was confirmed

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Fig. 3
figure 3

A 67-year-old man with uncontrolled hypertension and right adrenal mass on CT. The 24-h urinary metanephrines were elevated. MIP 68Ga-DOTANOC PET (a) image showed mildly increased abnormal tracer uptake in the right suprarenal region (arrow). Axial non-contrast CT (b) image of the abdomen shows a right adrenal mass (arrow) with areas of calcification and cystic degeneration. The mass shows mild 68Ga-DOTANOC uptake (SUVmax 1.6) on PET (c) and PET/CT (d) images (arrow). The patient underwent surgery and postoperative histopathology confirmed the diagnosis of pheochromocytoma

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Fig. 4
figure 4

A 56-year-old man with left adrenal incidentaloma on CT and elevated plasma norepinephrine. MIP 68Ga-DOTANOC PET image (a) and anterior 131I-MIBG scintigraphy image (b) are normal. On PET/CT image the left adrenal mass (c, arrow) does not show any significant 68Ga-DOTANOC uptake. Similarly, on SPECT/CT image no 131I-MIBG uptake is seen in the left adrenal mass (d, arrow). Postoperative histology revealed pheochromocytoma

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Fig. 5
figure 5

A 27-year-old man with headache, palpitations, and uncontrolled hypertension, along with right adrenal mass and multiple hepatic lesions on CT. MIP PET image (a) shows 68Ga-DOTANOC uptake in right adrenal mass (bold arrow), with multiple liver metastases (broken arrows), mediastinal paraganglioma (arrowhead), and pulmonary metastases (arrows). Axial PET/CT image (c) shows 68Ga-DOTANOC avid right adrenal mass (bold arrow) and liver metastases (broken arrows). Anterior 131I-MIBG scintigraphy image (b) shows only the left adrenal mass (bold arrow). On axial SPECT/CT image (d) only the 131I-MIBG avid left adrenal mass is seen (bold arrow). Biopsy from the liver lesions confirmed metastatic pheochromocytoma and the patient is undergoing peptide receptor radionuclide therapy

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Table 6 Comparative diagnostic accuracy of 68Ga-DOTANOC PET/CT and 131I-MIBG imaging on lesion wise analysis (results with 95 % confidence interval)
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MEN2 syndrome

In patients with MEN2, both68Ga-DOTANOC PET/CT and 131I-MIBG were available for 14/18 adrenal lesions. 68Ga-DOTANOC PET/CT was TP in ten and TN in four, while 131I-MIBG was TP in eight, TN in four, and FN in two. On lesion-based analysis no significant difference was seen between 68Ga-DOTANOC PET/CT and 131I-MIBG (p = 0.500). 131I-MIBG imaging demonstrated MTC in only one of four patients with MEN syndrome and failed to show neck node metastasis from MTC in one patient. All these MTC lesions were positive on 68Ga-DOTANOC PET/CT.

Malignant pheochromocytoma

Comparable 68Ga-DOTANOC PET/CT and 131I-MIBG images were available for five of seven patients (five adrenal lesions) with malignant pheochromocytoma. While 68Ga-DOTANOC PET/CT was positive for pheochromocytoma in all, 131I-MIBG was positive in three of five (60 %). In addition, 131I-MIBG imaging failed to show metastatic disease in three of five patients (60 %) with malignant pheochromocytoma, all of which were picked up by 68Ga-DOTANOC PET/CT.

Discussion

Pheochromocytomas routinely express SSTRs, predominantly SSTR3 and to some extent SSTR2 [14]. This forms the basis of SSTR-based SPECT and PET imaging in pheochromocytoma. Results of 111In-octreotide SPECT imaging in pheochromocytoma have generally been poor and inferior to MIBG imaging, with better results reported for malignant than benign pheochromocytoma [21]. Apart from the issue of limited resolution, this might have also been because of predominant affinity of 111In-octreotide towards SSTR2, rather than SSTR3 [22]. More recently SSTR-based PET/CT imaging of pheochromocytoma has been attempted using 68Ga-DOTA-peptides with encouraging results [15–19]. PET/CT imaging with these agents has already been shown to be superior to 111In-octreotide SPECT [23], though data pertaining specifically to pheochromocytoma are lacking. Among the 68Ga-DOTA-peptides, 68Ga-DOTANOC appears to be of particular interest because of its broader SSTR affinity, including intermediate to low affinity for SSTR3 [24, 25], the predominant subtype in most pheochromocytomas [14]. Surprisingly, most of the previous studies have employed 68Ga-DOTATOC [17] or 68Ga-DOTATATE [15, 16, 19] for imaging of pheochromocytoma, both of which have no significant affinity for SSTR3. Moreover, these studies suffered from the drawbacks of small sample sizes and mixed patient populations. To address these limitations, the present study assessed the diagnostic accuracy of 68Ga-DOTANOC PET/CT in a large population of patients with suspected pheochromocytoma. The present study differs from the pilot study conducted at our center by Naswa et al. [18] in certain important aspects. First is the larger sample size. Second, the present study evaluated an exclusive population of pheochromocytoma, while that by Naswa et al. [18] evaluated a mixed population of pheochromocytoma and paraganglioma. Third, we have also done in-depth analysis of SUV parameters, which was not attempted in the pilot study.

In the present study, 68Ga-DOTAOC PET/CT showed high diagnostic accuracy on both patient-based and lesion-based analysis (88.7 and 90 %, respectively). It was FP only for three adrenal lesions (size <1.5 cm), all of which turned out to be benign adenoma at histopathology. Two factors probably accounted for the FP results. First, since high 68Ga-DOTANOC uptake is seen in normal adrenals [26], differentiation of tumor uptake from tracer uptake in normal adrenal medulla is sometimes difficult, especially if the adrenal lesion is small. Second, some of the cortical adenomas can also demonstrate low-grade SSTR expression [27], resulting in FP findings. Because we did not have the SSTR profile of the resected specimens, we were not able to confirm these hypotheses in the present study. 68Ga-DOTANOC PET/CT was FN for three lesions. Definite adrenal nodule on CT was seen in only one of these four lesions, with the remaining three showing asymmetrical thickening. In fact, 68Ga-DOTANOC PET/CT was interpreted as negative for all 16 lesions without adrenal nodule/mass on CT. This is because of the limitation that it is not always possible to differentiate physiological from pathological uptake at visual PET analysis alone if CT does not show a definite mass or nodule. Therefore, 68Ga-DOTANOC PET/CT seems to be most useful when there is a definite adrenal mass or nodule at CT in the clinical setting of pheochromocytoma. The values of diagnostic accuracy reported in this study are lower than those of Naswa et al. [18]. The main reason for this difference is probably the preponderance of paraganglioma in their study population. On 68Ga-DOTANOC PET/CT, evaluation and identification of lesions at extra-adrenal sites is easier due to the lack of physiological tracer uptake. In addition, it is known that paragangliomas show higher levels of SSTR expression than pheochromocytomas. At semiquantitative analysis, wide variation was seen in SUV parameters for the tumors as well as normal adrenals. However, a major inference that could be derived is that pheochromocytomas have higher SUV parameters than other adrenal lesions, reconfirming high in vivo SSTR expression. Although there was significant difference between the SUVmax of tumors with paired and unpaired normal adrenal glands (p = 0.002 and 0.026, respectively), considerable overlap was seen between these values. Using ROC analysis we were able to find significant cutoffs for all SUV parameters for differentiating pheochromocytoma from other adrenal lesions. Among these, tumor SUVmax/SUVliver showed the highest diagnostic accuracy. However, the sensitivity and specificity of these SUV parameter cutoffs is only modest and inferior to visual analysis. Hence, the proposed thresholds might not be suitable for routine application in clinical practice.

In patients with MEN2 68Ga-DOTANOC PET/CT showed excellent results for detection of pheochromocytoma. There were no FP or FN results, thus showing the utility of 68Ga-DOTANOC PET/CT in MEN2 with suspected pheochromocytoma. However, all these patients had clinical/biochemical suspicion along with suspicious adrenal lesions at CT. Hence, whether the same success can be replicated in screening of asymptomatic cases with MEN2 needs to be established. 68Ga-DOTANOC PET/CT also detected associated MTC in five patients, for which it has known utility [28]. The SUVmax and SUVmean of the adrenal tumors in patients with MEN2 were significantly higher than sporadic tumors. Although the exact cause of this finding is unclear, this finding has also been previously reported in a rat model [29]. 68Ga-DOTANOC PET/CT also showed excellent results in patients with malignant pheochromocytoma. Primary tumor as well as metastasis was identified in all seven patients. Similar results were also reported by Kroiss et al. [17] in their study in patients with metastatic pheochromocytoma and neuroblastoma. We found no significant difference between malignant and benign pheochromocytoma with respect to SUV parameters, probably reflecting overlap of SSTR expression.

On a lesion-based comparison, 68Ga-DOTANOC PET/CT showed a significantly higher accuracy as compared to 131I-MIBG (91.1 vs 66.6 %, p = 0.035). These findings are similar to those reported by Naswa et al. [18] and Maurice et al. [19]. However, in patients with MEN2, no significant difference was found between 68Ga-DOTANOC PET/CT and 131I-MIBG for adrenal lesions (p = 0.500). This equality is probably the result of high accuracy of MIBG imaging for detection of pheochromocytoma in MEN2 [30] coupled with the small number of MEN2 patients in the present study. While further studies are required to make definitive comment, given the fact that 68Ga-DOTANOC PET/CT is also useful for imaging MTC, it may be preferred over MIBG imaging in patients with MEN2. In patients with malignant pheochromocytoma 68Ga-DOTANOC PET/CT showed primary tumor and metastasis in all patients, while 131I-MIBG scintigraphy was negative for pheochromocytoma in two of five patients and metastasis in three of five patients. Given the small number of patients statistical comparison was not attempted. We would like to highlight that 131I-MIBG, not 123I-MIBG, was used in the present study. The latter allows a higher dose, gives a high photon flux, and provides better image quality. Unfortunately, 123I-MIBG is not available in our country and cannot be imported because of the short half-life (T 1/2 13 h) and high cost. One might argue that the use of 123I-MIBG might have altered our results. However, the superiority of 123I-MIBG over 131I-MIBG in pheochromocytoma is only marginal [31]. In addition, the sensitivity of 131I-MIBG for pheochromocytoma in the present study is similar to those reported for 123I-MIBG by Kroiss et al. (61.2 and 63.3 %, respectively) [17]. Therefore, it is unlikely that use of 123I-MIBG would have significantly altered the results. On the other hand, a recent study has demonstrated the superiority of 131I-MIBG SPECT/CT over SPECT and planar imaging in pheochromocytoma [8]. Hence, the lack of SPECT/CT in all patients might have compromised the performance of 131I-MIBG imaging in the present study.

Other PET tracers which can be employed for imaging of pheochromocytoma include 18F-FDG to assess glucose metabolism, 11C-HED and 18F-FDA for catecholaminergic phenotype, and 18F-FDOPA for assessing amine uptake and decarboxylation. The most commonly used PET tracer 18F-FDG has shown low sensitivity but high specificity, comparable to 123I-MIBG imaging in pheochromocytoma [9]. It is particularly useful in metastatic pheochromocytoma and might have played a complementary role to 68Ga-DOTANOC PET/CT in the present population. 18F-FDOPA PET/CT has demonstrated high sensitivity and specificity for pheochromocytoma [10]. Minimal uptake of 18F-FDOPA in normal adrenal glands is advantageous when interpreting PET/CT images for pheochromocytoma. 18F-FDA PET/CT also has demonstrated encouraging results in pheochromocytoma and it is superior to both 18F-FDOPA PET/CT and 123I-MIBG for metastatic lesions [11]. 11C-HED is another PET/CT tracer showing high accuracy for pheochromocytoma [12]. Given the high diagnostic accuracy shown by 68Ga-DOTANOC PET/CT in the present study, a head to head comparison with these other PET tracers is warranted to find the optimum agent for different subgroups of pheochromocytoma. The points in favor of 68Ga-DOTANOC are its easy generator-based synthesis as compared to difficult synthesis (18F-FDOPA, 18F-FDA) or need for on-site cyclotron (11C-HED) for other tracers. Additionally, 68Ga-DOTANOC PET/CT can help in selection of patients (inoperable/metastatic) for peptide receptor radionuclide therapy, which is currently not possible with other PET tracers.

A few limitations of the present study must be acknowledged. First is the retrospective design. Second, histopathological diagnosis was not available for all the adrenal lesions. Although this would have been ideal, it was not ethically feasible. Hence, we employed a combination of clinical, biochemical, and imaging follow-up of at least 6 months to confirm or rule out pheochromocytoma, which is an accepted method. Third, 131I-MIBG SPECT/CT images were not available for all patients, as at our center, like most others, the decision to perform SPECT/CT is guided by planar imaging. Finally, the lack of knowledge regarding the succinate dehydrogenase (SDH) status, which is pivotal to understanding the results of functional imaging of pheochromocytomas, was a major limitation of the present study. Germline mutations in SDH enzyme gene (especially subunit B) occur in a subset of patients with pheochromocytoma. SDH status appears to be a critical parameter determining the prognosis as well as selecting the best functional imaging agent for pheochromocytomas and paragangliomas [32, 33]. Future prospective studies addressing these shortcomings and comparing 68Ga-DOTANOC with other PET tracers are warranted.

Conclusion

68Ga-DOTANOC PET/CT demonstrates high diagnostic accuracy in patients with clinical/biochemical suspicion of pheochromocytoma and adrenal abnormality at contrast CT and is superior to 131I-MIBG imaging for this purpose. Best results of 68Ga-DOTANOC PET/CT are seen in patients with MEN2-associated and malignant pheochromocytoma.