PET/CT comparing ⁶⁸Ga-DOTATATE and other radiopharmaceuticals and in comparison with CT/MRI for the localization of sporadic metastatic pheochromocytoma and paraganglioma

Abstract

Purpose

Pheochromocytomas/paragangliomas (PPGLs) and their metastases are tumors that predominantly express somatostatin receptor 2 (SSR2). ⁶⁸Ga-DOTA(0)-Tyr(3)-octreotate (⁶⁸Ga-DOTATATE) is a PET radiopharmaceutical with both high and selective affinity for SSRs. The purpose of this study was to evaluate the utility of ⁶⁸Ga-DOTATATE in comparison with other specific and nonspecific radiopharmaceuticals recommended in the current guidelines for the localization of metastatic sporadic PPGL by PET/CT.

Methods

This prospective study included 22 patients (15 men, 7 women; aged 50.0 ± 13.9 years) with confirmed metastatic PPGL, a negative family history for PPGL, and negative genetic testing, who underwent ⁶⁸Ga-DOTATATE, ¹⁸F-fluoro-2-deoxy-D-glucose (¹⁸F-FDG) PET/CT, and CT/MRI. Only 12 patients underwent an additional ¹⁸F-fluorodihydroxyphenylalanine (¹⁸F-FDOPA) PET/CT scan and only 11 patients underwent an additional ¹⁸F-fluorodopamine (¹⁸F-FDA) PET/CT scan. The rates of detection of metastatic lesions were compared among all the imaging studies. A composite of all functional and anatomical imaging studies served as the imaging comparator.

Results

⁶⁸Ga-DOTATATE PET/CT showed a lesion-based detection rate of 97.6 % (95 % confidence interval, CI, 95.8 – 98.7 %). ¹⁸F-FDG PET/CT, ¹⁸F-FDOPA PET/CT, ¹⁸F-FDA PET/CT, and CT/MRI showed detection rates of 49.2 % (CI 44.5 – 53.6 %; p < 0.01), 74.8 % (CI 69.0 – 79.9 %); p < 0.01), 77.7 % (CI 71.5 – 82.8 %; p < 0.01), and 81.6 % (CI 77.8 – 84.8 %; p < 0.01), respectively.

Conclusion

The results of this study demonstrate the superiority of ⁶⁸Ga-DOTATATE PET/CT in the localization of sporadic metastatic PPGLs compared to all other functional and anatomical imaging modalities, and suggest modification of future guidelines towards this new imaging modality.

Introduction

Pheochromocytomas/paragangliomas (PPGLs) are tumors derived from sympathetic tissue in adrenal or extraadrenal abdominal locations or from parasympathetic tissue in the thorax, head, or neck [1]. More than 35 % of PPGLs are hereditary [2], and patients with hereditary tumors that have underlying succinate dehydrogenase subunit B (SDHB) mutations are at the highest risk of developing metastatic disease [3]. However, 50 % of metastatic PPGLs occur in patients with sporadic disease, in whom no mutation can be found [4].

PPGLs overexpress somatostatin receptors (SSR), especially SSR2 [5], and the recently developed ⁶⁸Ga-labeled DOTA peptides have been shown to be far superior to ¹¹¹In-DTPA-octreotide (Octreoscan^®) for the detection of neuroendocrine tumor (NET) lesions [6]. A number of promising studies utilizing ⁶⁸Ga-DOTA peptide imaging in mostly mixed populations of patients with PPGL, including patients with sympathetic and parasympathetic PPGLs, have recently been published [7-12], including a study by our group which focused exclusively on SDHB mutation-related metastatic PPGLs [13]. However, a prospective evaluation of ⁶⁸Ga-DOTA(0)-Tyr(3)-octreotate (⁶⁸Ga-DOTATATE) focusing exclusively on patients with sporadic metastatic PPGLs has not so far been performed.

Since proper staging and early detection of metastatic disease are key factors in choosing an appropriate treatment plan, in follow-up, and in predicting outcome in these patients [14], the primary goal of this study was to evaluate the diagnostic utility of ⁶⁸Ga-DOTATATE PET/CT in this patient group. Secondarily, since SDHB mutation-related PPGLs have different functional imaging signatures compared with sporadic metastatic PPGLs [15] and have recently been shown to have higher SSR expression than sporadic tumors [16], it was also of great interest to determine whether and/or how these differences would affect the relative diagnostic performance of ⁶⁸Ga-DOTATATE in this patient group compared to metastatic PPGLs with underlying SDHB mutation.

Our third goal was to evaluate these patients for their potential eligibility for peptide receptor radionuclide therapy (PRRT), since DOTA peptides can also be labeled with therapeutic β-emitters such as ¹⁷⁷Lu and ⁹⁰Y. Treatment options are otherwise very limited in patients with metastatic PPGLs, since they often show only faint or even absent ^123/131I-metaiodobenzylguanidine (MIBG) uptake [17, 18] and are therefore not eligible for ¹³¹I-MIBG treatment. In those who show relevant ^123/131I-MIBG uptake, the treatment response is only about 30 % [19]. Furthermore, the use of chemotherapy with cyclophosphamide, vincristine and dacarbazine (CVD; response rate about 37 % [20]) is reserved for patients with rapidly growing tumors or extensive organ tumor burden (especially in the liver) and is limited by treatment-related toxicity.

In this study, we compared ⁶⁸Ga-DOTATATE PET/CT with ¹⁸F-fluoro-2-deoxy-D-glucose (¹⁸F-FDG) PET/CT (¹⁸F-FDG being the currently best available and recommended radiopharmaceutical for metastatic PPGL imaging [21]) and CT/MRI. Additional comparisons with ¹⁸F-fluorodihydroxyphenylalanine (¹⁸F-FDOPA) and ¹⁸F-fluorodopamine (¹⁸F-FDA) were possible in only 12 and 11 patients, respectively. Because histological proof was not feasible in many metastatic lesions, the composite of both anatomical and all functional imaging tests was used as the imaging comparator as described previously [13] and as supported by several investigators [22].

Materials and methods

Patients

Between January 2014 and July 2015, 22 consecutive patients (15 men, 7 women; mean age 50.0 ± 13.9 years) with apparent sporadic metastatic PPGL were prospectively evaluated at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) at the National Institutes of Health (NIH). All patients had proven PPGL based on histopathology. All patients had a negative family history of PPGL and underwent genetic testing with negative results (detailed results are provided in Table 1). The study protocol was approved by the institutional review board of the Eunice Kennedy Shriver NICHD (protocol 00-CH-0093) and the NIH Radiation Safety Committee. All patients provided written informed consent for all clinical, genetic, biochemical, and imaging studies for their PPGLs.The mean age of the patients at diagnosis of the primary PPGL was 41.2 ± 15.6 years. Patient characteristics are summarized in Table 1.

Table 1.

Patient characteristics

Patient no.	Sex	Tested negative	Age (years)		Location of primary	Hypersecretion	Time to metastasis (years)	Location of metastases
			Diagnosis	Time of study
1	m	SDHx, VHL	61	75	Right adrenal	NM, NE, DA, CgA	12	A/P
2	f	SDHx	52	55	Left adrenal	NM, NE, CgA	3	A/P, B
3	f	SDHx	54	54	Left para-adrenal	NM, NE, CgA	0	A/P, B
4	m	SDHx, MEN, VHL, TMEM 127	20	37	Right para-adrenal	NM	0	A/P, B, Li, Lu
5	m	SDHx, MEN, VHL	27	30	Unknown	NE, NM, DA, CgA	0	A/P, B, Li, Me
6	f	SDHx	21	46	Right glomus jugulare	None	9	A/P, B, Me, Ne
7	f	SDHx, MEN, VHL, MAX, TMEM 127	52	64	Left adrenal	NM, NE, DA, MTT, CgA	6	A/P, B, Li, Lu
8	f	SDHx, MAX	38	47	Left adrenal	NM, MN, CgA	7	B
9	f	SDHx	12	31	Left para-adrenal	CgA,	4	A/P, B, Lu
10	m	SDHx	56	59	Right adrenal	NM, MN, NE, DA, CgA	0	A/P, B, Lu, Ne
11	m	SDHx	42	52	Unknown	DA, CgA, MTT	5	A/P, B, Lu, Me, Ne
12	m	SDHx	49	52	Right retroperitoneal	CgA	0	B, Li
13	m	SDHx, VHL	54	61	Left adrenal	NM, NE, CgA, DA	0	A/P, B, Li, Lu, Me
14	m	SDHx, MAX	70	73	Left adrenal	NM, NE, CgA, DA	0	A/P, Lu, Me
15	m	SDHx	34	35	Left retroperitoneal	NM, NE, MN, Epi, DA, CgA	0	A/P, B, Li, Lu
16	m	SDHx	31	43	Right adrenal	NM, NE, DA, CgA	6	A/P, B, Me
17	m	SDHx, VHL	23	25	Right adrenal	NM, NE, DA, CgA, MTT	0	A/P, B, Li, Lu
18	m	SDHx	38	39	Right para-adrenal	NM, CgA	0	A/P, B, Li, Me
19	m	SDHx	43	64	Right adrenal	NM, NE, MN, Epi, DA, CgA, MTT	15	A/P, B
20	m	SDHx	34	41	Left adrenal	MTT	5	A/P, B
21	f	SDHx	63	64	Left adrenal	NM, NE, Epi, CgA, MTT	0	B, Li
22	m	SDHx	37	39	Right adrenal	NM, DA	2	B, Li, Lu

A/P abdominal/pelvic compartment, B bones, CgA chromogranin A, DA dopamine, Epi epinephrine, Li liver, Lu lungs, m male, MAX myc-associated factor X, Me mediastinum, MTT methoxytyramine, Ne neck, NE norepinephrine, NM normetanephrine, TMEM 127 trans-membrane protein 127

Imaging techniques

CT and MRI scans of the neck, chest, abdomen, and pelvis were performed as previously described [13]. All 22 patients underwent ⁶⁸Ga-DOTATATE and ¹⁸F-FDG PET/CT, and CT/MRI. In addition, 12 patients also underwent ¹⁸F-FDOPA PET/CT and 11 underwent ¹⁸F-FDA PET/CT. All imaging studies were performed within a median of 8.5 days.

PET/CT scans from the upper thighs to the skull were performed 60 min, 60 min, 30 min, and approximately 8 min after intravenous injection of ⁶⁸Ga-DOTATATE, ¹⁸F-FDG, ¹⁸F-FDOPA, and ¹⁸F-FDA at mean administered activities of 191.4±8.3 MBq, 316.5±59.4 MBq, 466.3±13.0 MBq, and 39.3 ± 0.7 MBq, respectively. Carbidopa (200 mg) was administered orally 60 min before each ¹⁸F-FDOPA scan [23]. All PET/CT scans were performed on a Siemens Biograph-mCT 64 scanner and a Biograph-mCT 128 PET/CT scanner (Siemens Medical Solutions). PET images were reconstructed using an iterative algorithm provided by the manufacturer, also utilizing point spread function and time of flight. Low-dose CT scans for attenuation correction and anatomical coregistration were performed without administration of contrast agent and were used for anatomical localization.

Analysis of data

⁶⁸Ga-DOTATATE PET/CT studies were read independently by two nuclear medicine physicians blinded to all imaging and clinical data except the diagnosis, sex, and age of the patient. Maximal standardized uptake values (SUV_max) were determined and focal areas of abnormal uptake with a higher SUV_max than surrounding tissue were considered as lesions. In all other imaging studies, physicians were blinded to ⁶⁸Ga-DOTATATE PET/CT and clinical data except for diagnosis, sex and age of the patient, and previous imaging studies. The composite of anatomical and all performed functional imaging tests was considered the imaging comparator. A positive result with at least two different functional imaging modalities or at least one functional imaging study and CT/MRI was counted as true disease, whereas a lesion detected only on CT/MRI or only with one functional imaging modality, while negative on all other used imaging tests, was considered a false-positive imaging result. This approach is consistent with our previously used imaging comparator [13] and is consistent with the recommendation of Hofman and Hicks for studies involving patient cohorts in whom histological proof is neither feasible nor ethical [22].

For regional analysis, adrenal glands, liver, abdominal/pelvic compartments (excluding adrenal glands and liver), lungs, mediastinum, and bone were analyzed separately. A patient or region was considered positive regardless of the number of positive findings. Per patient, per region, and per lesion analyses were performed. If the number of lesions in a region exceeded 15, the count was truncated at 15. Soft tissue lesions in the neck (due to their parasympathetic origin) as well as skull and extremity lesions, for which anatomical correlation and/or correlation on ¹⁸F-FDG imaging was not available, were excluded from evaluation.

Statistics

Results are given as means with 95 % confidence intervals (CIs) unless stated otherwise. For statistical analysis, the McNemar test was used to compare detection rates between ⁶⁸Ga-DOTATATE PET/CT and the other imaging modalities. Two-sided p values <0.05 were considered significant.

Results

On ⁶⁸Ga-DOTATATE PET/CT, 450 out of 461 lesions (97.6 %, CI 95.8 – 98.7 %) with a mean SUV_max of 51.7 ± 49.2 were identified compared with the defined imaging comparator. ¹⁸F-FDG, ¹⁸F-FDOPA and ¹⁸F-FDA PET/CT, and CT/MRI showed detection rates of 49.2 % (CI 44.5 – 53.6 %; p < 0.01), 74.8 % (CI 69.0 – 79.9 %; p < 0.01), 77.7 % (CI 71.5 – 82.8 %; p < 0.01), and 81.6 % (CI 77.8 – 84.8 %; p < 0.01), respectively. Significantly more lesions were identified on ⁶⁸Ga-DOTATATE PET/CT compared with all other functional imaging modalities and with CT/MRI (two-sided p < 0.01 for each imaging modality compared with ⁶⁸Ga-DOTATATE PET/CT). Lesion-based findings are summarized in Tables 2 and 3. Metastatic lesions were found in the mediastinum, lungs, liver, abdominal/pelvic compartment, and bones. Those in the mediastinum and abdominal/pelvic compartment were consistent with locations in lymph nodes. ⁶⁸Ga-DOTATATE missed six liver lesions (0.75 ± 0.15 cm) which were positive on ¹⁸F-FDOPA and anatomical imaging, one lung lesion which was positive on ¹⁸F-FDG and anatomical imaging, and four lung lesions which were positive on ¹⁸F-FDOPA and anatomical imaging studies (0.42 ± 0.11 cm). A lesion-based evaluation excluding the patients who underwent only ⁶⁸Ga-DOTATATE PET/CT, ¹⁸F-FDG PET/CT and CT/MRI did not lead to any significant statistical change.

Table 2.

Numbers of lesions identified on ⁶⁸Ga-DOTATATE, ¹⁸F-FDG, ¹⁸F-FDOPA and ¹⁸F-FDA PET/CT, and CT/MRI compared to lesions identified by the imaging comparator

Lesion location	68Ga-DOTATATE PET/CT	18F-FDG PET/CT	18F-FDOPA PET/CTa	18F-FDA PET/CTa	CT/MRI
All compartments	450/461	226/461	181/242	160/206	376/461
Mediastinum	46/46	26/46	17/24	21/21	27/46
Lungs	89/94	52/94	52/53	26/38	89/94
Abdomen	74/74	42/74	30/41	35/38	57/74
Liver	42/48	6/48	11/13	9/13	45/48
Bone	199/199	100/199	71/111	69/96	158/199

^aNot all patients underwent PET/CT scans with these radiopharmaceuticals

Table 3.

Lesion detection rates for ⁶⁸Ga-DOTATATE, ¹⁸F-FDG, ¹⁸F-FDOPA and ¹⁸F-FDA PET/CT, and CT/MRI

Lesion location	68Ga-DOTATATE PET/CT		18F-FDG PET/CT		18F-FDOPA PET/CT		18F-FDA PET/CT		CT/MRI
	Detection rate (%)	95 % CI (%)	Detection rate (%)	95 % CI (%)	Detection rate (%)	95 % CI (%)	Detection rate (%)	95 % CI (%)	Detection rate (%)	95 % CI (%)
All compartments	97.6	95.8 – 98.7	49.2	44.5 – 53.6	74.8	69.0 – 79.9	77.7	71.5 – 82.8	81.6	77.8 – 84.8
Mediastinum	100	92.3 – 100	56.5	42.3 – 69.8	70.8	50.8 – 85.1	100	84.5 – 100	58.7	44.3 – 71.7
Lungs	94.7	95.1 – 97.1	55.3	45.3 – 65.0	98.1	90.1 – 99.7	68.4	52.5 – 80.9	94.7	88.2 – 97.7
Abdomen	100	95.1 – 100	56.8	45.3.4 – 67.4	73.2	58.1 – 84.3	92.1	79.2 – 97.3	77.0	66.3 – 85.1
Liver	87.5	75.3 – 94.1	12.5	5.9 – 24.7	84.5	57.8 – 95.7	69.2	42.4 – 87.3	93.8	83.2 – 97.8
Bone	100	98.1 – 100	50.3	43.4 – 57.1	64.0	54.7 – 72.3	71.2	62.2 – 79.9	79.4	73.3 – 84.4

Besides the 450 lesions detected on ⁶⁸Ga-DOTATATE PET/CT and confirmed by the defined imaging comparator, 55 additional lesions were identified on ⁶⁸Ga-DOTATATE PET/CT that could not be confirmed by any of the other imaging studies and therefore were not included amongst the 461 lesions used in the comparator and counted as false positive (4 mediastinal lymph nodes, 11 retroperitoneal and pelvic lymph nodes, and 40 bone lesions; mean SUV_max 25.1 ± 34.9). On CT/MRI, 13 lesions were reported that were not positive on any functional imaging study (eight lung nodules, and five liver lesions). One abdominal lymph node and three mediastinal lymph nodes were positive only on ¹⁸F-FDG PET. One bone lesion was positive only on ¹⁸F-FDOPA PET/CT. ¹⁸F-FDA PET/CT did not show any lesions that were not also seen on other studies.

The per-patient detection rates for ⁶⁸Ga-DOTATATE, ¹⁸F-FDG, ¹⁸F-FDOPA and ¹⁸F-FDA PET/CT, and CT/MRI were 100% (22/22 patients, 95 % CI 85.1 – 100 %), 90.9 % (20/22, 95 % CI 72.2 – 97.5 %), 91.7 % (11/12, 95 % CI 64.6 – 98.5 %), 90.9 % (10/11, 95 % CI 62.3 – 98.4 %), and 100 % (22/22, 95 % CI 85.1 – 100 %), respectively. The per region detection rates for ⁶⁸Ga-DOTATATE, ¹⁸F-FDG, ¹⁸F-FDOPA and ¹⁸F-FDA PET/CT, and CT/MRI were 97.0 % (identifying 65/67 involved regions, 95 % CI 89.8 – 99.2 %), 74.6 % (50/67, 95 % CI 87.7 – 99.6 %), 81.6 % (31/38, 95 % CI 66.6 – 90.8 %), 78,8 % (26/33, 95 % CI 62.3 – 89.3 %), and 83.6 % (56/67, 95 % CI 72.9 – 90.6 %), respectively. PET imaging examples comparing ⁶⁸Ga-DOTATATE, ¹⁸F-FDG, ¹⁸F-FDOPA, and ¹⁸F-FDA PET/CT are shown in Figs. 1 and 2.

Fig. 1.

A 39-year-old man with sporadic metastatic paraganglioma, who was first diagnosed with a 9.5-cm paraganglioma involving the left kidney, and bone metastases in 2014. The ⁶⁸Ga-DOTATATE (a), ¹⁸F-FDG (b), and ¹⁸F-FDA (d) PET images show very similar extensive metastatic disease involving bone, liver, and mediastinal and retroperitoneal lymph nodes. The ¹⁸F-FDOPA PET image (c) is almost negative

Fig. 2.

A 64-year-old man with sporadic metastatic paraganglioma, who was first diagnosed with a right adrenal pheochromocytoma in 1994 and metastatic disease to the bones in 2009. The ⁶⁸Ga-DOTATATE (a), ¹⁸F-FDOPA (c), and ¹⁸F-FDA (d) PET images show very similar extensive metastatic bone disease. The ¹⁸F-FDG PET image (b) is almost negative

Discussion

We evaluated ⁶⁸Ga-DOTATATE PET/CT in 22 patients with sporadic metastatic PPGLs in comparison with ¹⁸F-FDG, ¹⁸F-FDOPA and ¹⁸F-FDA PET/CT, and CT/MRI. The composite of both anatomical and all functional imaging tests was considered the imaging comparator [13, 22]. ⁶⁸Ga-DOTATATE PET/CT was significantly superior to all other imaging modalities in this study.

For functional imaging of metastatic PPGL, the genetic background and differentiation status of the tumor are the main factors influencing the uptake of radiopharmaceuticals [24]. ¹⁸F-FDG is a sensitive but nonspecific radiopharmaceutical, which accumulates in many malignant tumors and enters cells via glucose transporters [25]. Enhanced glucose correlates with the degree of dedifferentiation, possibly caused by the shift from oxidative phosphorylation to aerobic glycolysis (Warburg effect) [26], due to upregulation of hypoxic angiogenetic pathways via hypoxia-inducible factors [27], which are mainly seen in patients with an underlying SDHB germline mutation. Because it has been shown to be far superior to ¹²³I-MIBG (which was not evaluated in this study) in the diagnosis of metastatic PPGLs [15, 17, 28] and its broad availability, ¹⁸F-FDG PET/CT is the currently recommended functional imaging modality for diagnosing metastatic PPGL according to the Endocrine Society Clinical Practice guidelines [21]. However, the sensitivity of ¹⁸F-FDG PET/CT in patients with apparently sporadic PPGL is lower than in patients with an underlying SDHB mutation [17, 24]. In contrast, ¹⁸F-FDOPA, a highly specific radiopharmaceutical for catecholamine synthesis and targeting cells via the large amino acid transporter system [29], has shown very good results in detecting metastatic lesions in patients with sporadic PPGL [17], whereas the detection rate for metastatic lesions in SDHB mutation-related PPGL is poor [15, 17]. Accordingly, the guidelines of the European Association of Nuclear Medicine prefer ¹⁸F-FDOPA in metastatic PPGL in the absence of an underlying SDHB mutation [24]. ¹⁸F-FDA, which enters chromaffin cells via the norepinephrine transporter [30], has shown good detection rates for metastatic disease in patients with sporadic PPGL, whereas the reported results in SDHB mutation-related metastases have been less consistent [13, 15].

Given the differences in functional imaging signatures between sporadic and SDHB mutation-related metastatic PPGL, the reported higher expression of SSR2A and SSR3 in PPGLs with SDH deficiency compared to sporadic tumors [16], and the excellent performance of ⁶⁸Ga-DOTATATE for diagnosing SDHB mutation-related PPGL in our previous study [13], it was somewhat surprising that ⁶⁸Ga-DOTATATE performed similarly in sporadic disease. The lesions missed on ⁶⁸Ga-DOTATATE PET/CT were mainly located in the liver, a phenomenon that has been reported before in different NETs [31]. Kroiss et al. also demonstrated an overlap in SUVs between normal liver tissue and liver metastases of gastroenteropancreatic and non-gastroenteropancreatic NETs [32]. To avoid additional anatomical imaging, and considering the high sensitivity of MRI for liver lesions, PET/MRI might be an interesting and beneficial alternative in these patients in the future. Five lesions missed on ⁶⁸Ga-DOTATATE PET/CT were pulmonary lesions smaller than 0.6 cm, with four of them were positive on ¹⁸F-FDOPA. Thus, dedicated MRI and CT imaging of the liver and lungs in addition to ⁶⁸Ga-DOTATATE PET/CT is still needed as a first line investigation in order not to miss small lung metastases as well liver metastases. ⁶⁸Ga-DOTATATE PET/CT can also be used to determine which patients may benefit from PRRT or from treatment with cold SSR analogs, also including patients in whom the PPGL location or extension (especially in the skull base) cannot be accessed surgically by any approach [33].

In this study, the unverifiable lesions detected only on ⁶⁸Ga-DOTATATE PET/CT were primarily located in the skeleton and, much less frequently, in subcentimeter mediastinal and retroperitoneal lymph nodes. Likely, more bone lesions might have been confirmed by MRI, if additional MRI scans dedicated to the spine had been performed, since this modality is very sensitive in detecting replacement of bone marrow fat and hematopoietic cells by tumor tissue [34]. Additional lesions appearing only on PET/CT with ⁶⁸Ga-DOTA analogs compared to any other imaging comparator have previously been reported in several studies [13, 35, 36]. Despite the high specificity of ⁶⁸Ga-DOTATATE for NETs [37], false-positive findings in our study population cannot be excluded given our lack of histological proof.

The current management guidelines for PPGL do not yet take PET imaging with ⁶⁸Ga-DOTA peptides into consideration. Yet ⁶⁸Ga-DOTATATE PET/CT was superior to all radiopharmaceuticals used in this study including ¹⁸F-FDOPA and especially ¹⁸F-FDG, suggesting that ⁶⁸Ga-DOTATATE has the potential to affect patient treatment plans and outcomes by identifying not only more metastatic lesions but also additional involved sites of disease as compared with all other functional imaging modalities and CT/MRI.

Our study had certain limitations, including the relatively small number of patients, although this study is the largest to date that focused on ⁶⁸Ga-DOTA peptide imaging in this rare disease. Furthermore, ¹⁸F-FDOPA and ¹⁸F-FDA PET/CT scans could only be performed in 12 and 11 patients, respectively. On the one hand, this diminishes the importance of our results regarding comparison of ⁶⁸Ga-DOTATATE with these radiopharmaceuticals and on the other hand, might have also influenced the results of the comparison between ⁶⁸Ga-DOTATATE and ¹⁸F-FDG, since additional ¹⁸F-FDOPA and ¹⁸F-FDA scans might have led to a smaller number of false-positive lesions. Additionally, histological proof was neither feasible nor ethical for the vast majority of metastatic lesions. Although our chosen imaging comparator likely provides a close approximation of “truth”, false-positive and falsenegative findings cannot be excluded. In addition, our study was biased in that we limited our lesion counts to 15 per region, thus often underestimating the number of lesions seen.

In conclusion, this study clearly demonstrated the superiority of ⁶⁸Ga-DOTATATE PET/CT in detection of sporadic metastatic PPGL lesions over ¹⁸F-DOPA and ¹⁸F-FDA PET/CT, CT/MRI, and especially ¹⁸F-FDG PET/CT, which is supported by previous findings [7, 13]. Given the expected broader clinical availability of ⁶⁸Ga-DOTATATE along with the theranostic value of this radiopharmaceutical, a change in the clinical guidelines for functional imaging of metastatic PPGL especially from ¹⁸F-FDG towards ⁶⁸Ga-DOTA peptides is strongly suggested. The utility of ⁶⁸Ga-DOTA peptides in other genotypes and nonmetastatic PPGL, or for the evaluation of treatment response, needs to be further evaluated in the future.