Functional Imaging of SDHx-Related Head and Neck Paragangliomas: Comparison of ¹⁸F-Fluorodihydroxyphenylalanine, ¹⁸F-Fluorodopamine, ¹⁸F-Fluoro-2-Deoxy-d-Glucose PET, ¹²³I-Metaiodobenzylguanidine Scintigraphy, and ¹¹¹In-Pentetreotide Scintigraphy

Abstract

Rationale:

Accurate diagnosis of head and neck paragangliomas is often complicated by biochemical silence and lack of catecholamine-associated symptoms, making accurate anatomical and functional imaging techniques essential to the diagnostic process.

Methods:

Ten patients (seven SDHD, three SDHB), with a total of 26 head and neck paragangliomas, were evaluated with anatomical and functional imaging. This study compares five different functional imaging techniques [¹⁸F-fluorodihydroxyphenylalanine (¹⁸F-FDOPA) positron emission tomography (PET), ¹⁸F-fluorodopamine (¹⁸F-FDA) PET/computed tomography (CT), ¹⁸F-fluoro-2-deoxy-d-glucose (¹⁸F-FDG) PET/CT, ¹²³I-metaiodobenzylguanidine (¹²³I-MIBG) scintigraphy, and ¹¹¹In-pentetreotide scintigraphy] in the localization of head and neck paragangliomas.

Results:

Prospectively ¹⁸F-FDOPA PET localized 26 of 26 lesions in the 10 patients, CT/magnetic resonance imaging localized 21 of 26 lesions, ¹⁸F-FDG PET/CT localized 20 of 26 lesions, ¹¹¹In-pentetreotide scintigraphy localized 16 of 25 lesions, ¹⁸F-FDA PET/CT localized 12 of 26 lesions, and ¹²³I-MIBG scintigraphy localized eight of 26 lesions. Differences in imaging efficacy related to genetic phenotype, even in the present small sample size, included the negativity of ¹⁸F-FDA PET/CT and ¹²³I-MIBG scintigraphy in patients with SDHB mutations and the accuracy of ¹⁸F-FDG PET/CT in all patients with SDHD mutations, as compared with the accuracy of ¹⁸F-FDG PET/CT in only one patient with an SDHB mutation.

Conclusion:

Overall, ¹⁸F-FDOPA PET proved to be the most efficacious functional imaging modality in the localization of SDHx-related head and neck paragangliomas and may be a potential first-line functional imaging agent for the localization of these tumors.

Head and neck paragangliomas are tumors arising from the parasympathetic ganglia in the head and neck including the carotid bifurcations, the glomus jugulare, and the glomus vagale (1). Presumably because of biochemical silence, reflected by normal catecholamine and metanephrine levels (2), patients do not often complain of catecholamine-related signs and symptoms. Genetic predisposition to head and neck paragangliomas has been identified in the succinate dehydrogenase gene subunits B, C, and D (SDHB/SDHC/SDHD). SDHC and SDHD mutations are more commonly associated with head and neck paragangliomas than are SDHB mutations; however, head and neck paragangliomas have been identified in patients with SDHB gene mutations (3, 4). Diagnostic challenges with head and neck paragangliomas, such as biochemical silence, and therefore, a lack of classical symptoms associated with paragangliomas underscore the need for accurate and tumor-specific imaging techniques.

Anatomical and functional imaging is important in the localization and subsequent treatment of head and neck paragangliomas. Anatomical imaging, such as computed tomography (CT) and magnetic resonance imaging, is used for the initial localization of tumors, but its nonspecificity limits its efficacy in diagnosing a paraganglioma over another mass. On the other hand, functional imaging modalities can be used to differentiate between specific types of tumor because they target specific cell receptors such as cell membrane norepinephrine transporters, somatostatin receptors, as well as glucose and amino acid transporters that are thought to be up-regulated on paraganglioma cells (5).

Although previous studies have looked at the efficacy of various imaging techniques in localizing pheochromocytoma/paraganglioma, few looked specifically at functional imaging in head and neck paragangliomas (6–8). The aim of this study was to evaluate the efficacy of five different functional imaging techniques currently available at the National Institutes of Health [¹⁸F-fluorodihydroxyphenylalanine (¹⁸F-FDOPA) positron emission tomography (PET), ¹⁸F-fluorodopamine (¹⁸F-FDA) PET/CT, ¹⁸F-fluoro-2-deoxy-d-glucose (¹⁸F-FDG) PET/CT, ¹²³I-metaiodobenzylguanidine (¹²³I-MIBG) scintigraphy, and ¹¹¹In-pentetreotide scintigraphy] (9–15) in the localization of head and neck paragangliomas in a small cohort of SDHx patients and to provide recommendations to clinicians regarding the localization of these tumors.

Patients and Methods

Patients

Ten patients (nine males, one female) with head and neck paragangliomas were evaluated at the National Institutes of Health in an institutional review board-approved protocol, 00-CH-0093, between November 2007 and October 2010; informed written consent was provided and testing was performed. Of these 10 patients, five had a previous diagnosis of a head and/or neck tumor. The mean age at diagnosis was 38.4 yr (sd ± 16.8) with a range of 19–56 yr. Three patients (patients 5, 8, and 9) had metastatic disease [defined as pheochromocytomas/paragangliomas in sites outside of where chromaffin tissue is normally present, such as the lungs, bones, lymph nodes, and liver (16)] at the time of evaluation. These lesions were not analyzed in this study.

Seven patients had an underlying mutation in the SDHD gene and three patients in the SDHB gene.

Two of 26 lesions, in two patients (patients 1 and 7), were resected and pathologically confirmed as paragangliomas. Pathologic review of outside specimens from another three patients (patients 2, 3, and 10) also confirmed paragangliomas. The pathological review of the tumors of the final five patients was not performed because of the refusal of surgery (patients 4 and 6) or the contraindication for surgery due to the presence of other tumors (patients 5, 8, and 9).

Computed tomography and magnetic resonance imaging

CT of the neck was performed on all patients using high-speed multislice scanners: Philips Brilliance 64 (Best, The Netherlands), GE Lightspeed QX/I (General Electric, Milwaukee, WI), or Siemens Definition (Siemens Medical Solutions, Forchheim, Germany). CT scanning was performed after 130 ml infusion of an iv water-soluble nonionic iodine low-osmolality contrast agent (iopamidol 300 mg of iodine per milliliter [Isovue 300; Bracco Diagnostics, Princeton, NJ]) at 3–4 ml/sec, except one patient (patient 8) in whom iv contrast was not given due to impaired kidney function.

Magnetic resonance imaging (MRI) of the neck was performed on all patients using 1.5 Tesla or 3.0T Philips Achieva magnetic resonance scanners. The studies were performed after the injection of 0.2 ml/kg (0.1 mmol/kg) gadopentetate dimeglumine (Magnevist; Berlex, Wayne, NJ) or gadoversetamide (OptiMARK; Tyco Healthcare/Mallinckrodt, St. Louis, MO).

A single radiologist who was blinded to the results of other studies but was provided with a preliminary diagnosis of paraganglioma read the CT/MRI scans.

Functional imaging

¹⁸F-FDG and ¹⁸F-FDA PET/CT imaging were performed using a Discovery ST PET/CT scanner (General Electric Medical Systems) with a 15-cm axial field of view. The CT studies, used for attenuation correction and coregistration, were performed without contrast. Patients fasted for at least 6 h before injection of 555 MBq (15 mCi) ¹⁸F-FDG and for at least 6 h before the injection of 37 MBq (1 mCi) ¹⁸F-FDA. For ¹⁸F-FDG PET/CT, patients were scanned beginning 60 min after injection, whereas ¹⁸F-FDA PET/CT scanning began approximately 10 min after injection.

¹⁸F-FDOPA PET imaging was performed using an Advance scanner (General Electric Healthcare) with a 15-cm axial field of view and a rod source attenuation correction. Patients fasted for at least 6 h before injection of 444 MBq (12 mCi) of ¹⁸F-FDOPA. All patients were premedicated with 200 mg carbidopa 1 h before tracer injection. Patients were scanned starting 30 min after injection.

¹²³I-MIBG scintigraphy was performed approximately 24 h after an injection of 370 MBq (10 mCi) ¹²³I-MIBG. To protect the thyroid, patients were medicated with 100 mg saturated solution of potassium iodide by mouth twice a day for 4 d starting the night before the ¹²³I-MIBG injection. Planar and single-photon emission computed tomography (SPECT) images were obtained. Some patients underwent SPECT/CT scanning.

¹¹¹In-pentetreotide scintigraphy was performed approximately 4 h after an injection of 229.4 MBq (6.2 mCi) ¹¹¹In-pentetreotide. Planar imaging followed by SPECT or SPECT/CT was performed at 4 h with repeat SPECT or SPECT/CT at 24 h, as needed.

Patients' medications were reviewed before imaging to ensure that they were not taking drugs that would interfere with ¹²³I-MIBG scintigraphy or ¹⁸F-FDA PET/CT imaging studies.

All functional imaging studies were reviewed by a nuclear medicine physician. ¹⁸F-FDA PET/CT and ¹⁸F-FDOPA PET studies are considered research scans and were read in a blinded fashion. Lesions were graded on a scale of 0–5 with a grade of 4 or 5 indicating a definite abnormality and the presence of a lesion, as previously described (17).

Results

Nine patients underwent all five functional imaging scans and one patient (patient 4) underwent all scans but ¹¹¹In-pentetreotide scintigraphy. All 10 patients also underwent CT and MRI. All definite head and neck foci localized with functional imaging modalities were presumed to be true positive paragangliomas. A total of 26 head and neck lesions were found and named based on their anatomical location: 14 carotid body tumors, seven glomus jugulare tumors, four glomus vagale tumors, and one in the soft tissue of the neck above the level of the right carotid body at the level of C1. Clinical data are shown in Table 1.

Table 1.

Clinical characteristics

Pt	Sex	Age at diagnosis (yr)	Head and neck tumor location based on CT/MRI	Genotype	Biochemical phenotype
					Metastatic or other primary	NE (80–498 pg/ml)	EPI (4–83 pg/ml)	DA (3–46 pg/ml)	NMN (18–112 pg/ml)	MN (12–61 pg/ml)
1	M	23	2.0 × 1.2 cm R carotid body tumor	SDHD		239	18	14	50	54
2	M	25	1.8 × 2.0 cm R glomus jugulare tumor	SDHD	Second primary, cardiac	5324	24	203	1758	23
3	M	44	1.2 × 0.7 cm L carotid body tumor; 1.1 × 1.0 cm L carotid body tumor (two additional lesions localized on 18F-FDOPA PET: one in the neck on the right and one in the neck on the left at the level of C1)	SDHD		639	14	425	291	21
4	M	74	1.0 × 0.8 cm R carotid body tumor	SDHB		228	62	14	51	51
5	F	56	2.4 × 1.8 cm R carotid body tumor; 2.2 × 2.8 cm L carotid body tumor	SDHD	Metastatic	1539	<5	20	684	13
6	M	19	2.0 × 1.7 cm R glomus jugulare tumor; 1.0 × 1.0 cm L glomus jugulare tumor; 3.6 × 2.3 cm L glomus vagale tumor; 2.6 × 1.7 cm R carotid body tumor; 3.1 × 2.6 cm L carotid body tumor	SDHD		296	10	437	97	31
7	M	33	0.6 × 0.6 cm R carotid body tumor	SDHB		175	8	8	22	27
8	M	29	3.2 × 2.6 cm R carotid body tumor; 2.4 × 1.9 cm L carotid body tumor	SDHB	Metastatic	12668	<26	2474	2679
9	M	38	3.8 × 2.8 cm R carotid body tumor; 3.1 × 2.3 cm L carotid body tumor; 4.2 × 2.5 cm R glomus vagale tumor (three additional lesions localized on 18F-FDOPA PET: two in the jugular fossa on each side and one in the soft tissue of the neck on the left)	Unknown	Metastatic	1083	<11	17	456	<5
10	M	43	2.3 × 1.4 cm R carotid body tumor; 1.5 × 0.9 cm L glomus vagale tumor; 11.5 × 0.9 cm R glomus jugulare tumor (one additional lesion localized on 18F-FDOPA PET in the L jugular fossa)	SDHD		481	11	123	62	40

Clinical characteristics at the time of the imaging studies, including the presence of pheochromocytoma/paraganglioma (metastatic or second primary) outside the head and neck paraganglioma being evaluated. Bold numbers indicate a value above the upper reference limit. DA, Dopamine; EPI, epinephrine; F, female; L, left; M, male; MN, metanephrine; NE, norepinephrine; NMN, normetanephrine; Pt, patient; R, right.

Prospectively, ¹⁸F-FDOPA PET identified 26 of 26 lesions (100%); CT/MRI identified 21 of 26 lesions (81%); ¹⁸F-FDG PET/CT identified 20 of 26 lesions (77%); ¹¹¹In-pentetreotide scintigraphy identified 16 of 25 lesions (64%); ¹⁸F-FDA PET/CT identified 12 of 26 lesions (46%); and ¹²³I-MIBG scintigraphy identified eight of 26 lesions (31%). One lesion initially not localized on CT/MRI was retrospectively found after functional imaging studies. No false-positive results were seen. Results are outlined in Table 2.

Table 2.

Number of lesions identified with each imaging modality

Pt	Sex	Age at diagnosis (yr)	Size (cm)	Lesion	CT/MRI	18F-FDG	18F-FDA	18F-FDOPA	123I-MIBG	111In-pentetreotide	18F-F-DOPA only
1	M	23	2.0 × 1.2	R CBT	+	+	0	+	0	+
2	M	25	1.8 × 2.0	R glomus jugluare	+	+	0	+	0	+
3	M	44	1.2 × 0.7	L CBT	+	+	0	+	0	0
			1.1 × 1.0	L CBT (level of C1)	+	+	0	+	0	0
			1.3 × 0.9	L glomus vagale	(+)	+	0	+	0	0
				R above CBT level	0	0	0	+	0	0	x
4	M	74	1.0 × 0.8	R CBT	+	0	0	+	0	ND
5	F	56	2.2 × 2.8	L CBT	+	+	0	+	0	+
			2.4 × 1.8	R CBT	+	+	0	+	0	+
6	M	19	3.1 × 2.6	L CBT	+	+	+	+	+	+
			2.6 × 1.7	R CBT	+	+	+	+	+	+
			3.6 × 2.3	L glomus vagale	+	+	+	+	+	+
			1.0 × 1.0	L glomus jugulare	+	+	+	+	+	+
			2.0 × 1.7	R glomus jugulare	+	+	+	+	0	0
7	M	33	0.6 × 0.6	R CBT	+	0	0	+	0	0
8	M	29	2.4 × 1.9	L CBT	+	+	0	+	0	+
			3.2 × 2.6	R CBT	+	+	+	+	+	+
9	M	38	3.1 × 2.3	L CBT	+	+	+	+	0	+
			3.8 × 2.8	R CBT	+	+	0	+	0	+
			4.2 × 2.5	R glomus vagale	+	+	+	+	+	+
				R glomus jugulare	0	0	+	+	0	0
				L glomus jugulare	0	0	0	+	0	0	x
10	M	43	2.3 × 1.4	R CBT	+	+	+	+	+	+
			1.5 × 0.9	L glomus vagale	+	+	+	+	0	+
			1.5 × 0.9	R glomus jugluare	+	+	+	+	+	+
				L glomus jugulare	0	0	0	+	0	0	x

The plus sign indicates positive localization of the lesion. F, Female; ¹¹¹In-pentetreotide, ¹¹¹In-pentetreotide scintigraphy; M, male; ND, scan not performed (not done); Pt, patient.

For three of the lesions, ¹⁸F-FDOPA PET was the only modality that was positive. Although no actual measurements are available for these lesions because they were localized using only a PET scanner, nuclear medicine physicians describe them to be relatively small lesions. Most lesions were detected by at least two modalities including CT/MRI. In two patients with SDHB mutations (patients 4 and 7), ¹⁸F-FDOPA PET was the only functional imaging modality to identify the carotid body tumors, although one patient (patient 4) did not undergo ¹¹¹In-pentetreotide scintigraphy. In the third patient with an SDHB mutation (patient 8), bilateral carotid body tumors were identified with ¹⁸F-FDOPA PET, ¹⁸F-FDG PET/CT, and ¹¹¹In-pentetreotide scintigraphy; ¹⁸F-FDA PET/CT and ¹²³I-MIBG scintigraphy each identified only one tumor (Fig. 1). Of the seven patients with SDHD mutations, three patients (patients 6, 9, and 10) showed positive results in at least one lesion with all modalities. In the other four patients with SDHD mutations, ¹⁸F-FDA PET/CT and ¹²³I-MIBG scintigraphy were negative in all lesions, and one patient (patient 3) had a totally negative ¹¹¹In-pentetreotide scintigraphy scan.

Fig. 1.

A, Patient 8 with bilateral carotid body tumors. Transverse sections of CT scan and the five functional imaging scans are shown. The CT scan, ¹⁸F-FDOPA PET, ¹⁸F-FDG PET/CT, and ¹¹¹In-pentetreotide scintigraphy all successfully show the bilateral carotid body tumors (arrows). ¹⁸F-FDA PET/CT and ¹²³I-MIBG scintigraphy both show only the right carotid body tumor. B, Patient 7 with right 6-mm carotid body tumor. Transverse sections of the CT scan and four functional imaging modalities and an anterior planar image of the ¹¹¹In-pentetreotide scan (SPECT of this level not performed) are shown. The CT and ¹⁸F-FDOPA PET successfully demonstrate the right carotid body tumor (arrows); no other functional imaging studies demonstrate this tumor.

Interestingly, the tumors of two patients with SDHB mutations and a silent biochemical phenotype showed no uptake of ¹⁸F-FDG, whereas the patient with a noradrenergic and dopaminergic secretory profile did show uptake of ¹⁸F-FDG. The biochemical phenotype did not appear to correlate with the imaging of the head and neck tumors of patients with SDHD mutations.

Discussion

We present a comparison of five functional imaging techniques in the localization of SDHx-related head and neck paragangliomas. ¹⁸F-FDOPA PET, localizing 26 of 26 tumors, was found to be the best functional imaging modality for localizing SDHx-related head and neck paragangliomas. This was followed by CT/MRI localizing 21 of 26 tumors, ¹⁸F-FDG PET/CT localizing 20 of 26 tumors, ¹¹¹In-pentetreotide scintigraphy localizing 16 of 25 tumors, ¹⁸F-FDA PET/CT localizing 12 of 26 tumors, and ¹²³I-MIBG scintigraphy localizing eight of 26 tumors. Pheochromocytomas/paragangliomas are diagnosed based on biochemical and imaging studies, both anatomical and functional, which makes choosing an accurate imaging modality very important. Functional imaging modalities target tumor cells by different mechanisms. ¹⁸F-FDG targets the glucose pathway of cells (18, 19), whereas ¹⁸F-FDA and ¹²³I-MIBG target norepinephrine transporters (20, 21). ¹⁸F-FDOPA enters through amino acid transporters (22, 23), and ¹¹¹In-pentetreotide targets somatostatin receptors (24, 25). Four of these five techniques target pheochromocytoma/paraganglioma cells specifically.

Previous studies have demonstrated the efficacy of ¹⁸F-FDOPA PET in the localization of pheochromocytomas/paragangliomas in general (6, 15, 26), but few have focused specifically on head and neck paragangliomas (8, 27, 28). A study by Hoegerle et al. (8) evaluated 10 patients with suspected head and neck paragangliomas using MRI and ¹⁸F-FDOPA PET and were able to localize such tumors in eight patients with ¹⁸F-FDOPA PET. A case report by Brink et al. (27) also demonstrated successful imaging in an SDHD patient with bilateral carotid body tumors using ¹⁸F-FDOPA PET. Taieb et al. (28) evaluated nine patients with a pheochromocytoma/paraganglioma, including three with head and neck paragangliomas, and demonstrated ¹⁸F-FDOPA uptake in all head and neck paragangliomas present. None of these studies assessed the efficacy of ¹⁸F-FDOPA PET in patients with SDHx mutations specifically. In the present report, ¹⁸F-FDOPA PET was superior to all other functional imaging techniques studied and had 100% sensitivity, regardless of biochemical phenotype, tumor location, or genetic status.

Although ¹⁸F-FDG PET/CT is not pheochromocytoma/paraganglioma specific, its efficacy in localizing these tumors is well established (29), especially in the localization of SDHB-related lesions (17). Timmers et al. (17) described localization of two SDHB-related neck tumors using ¹⁸F-FDG PET/CT, and Taieb et al. (30) described four patients with head and/or neck tumors, two of whom had an SDHB mutation and were imaged on ¹⁸F-FDG PET/CT. In our patients, ¹⁸F-FDG PET/CT localized 20 of 26 lesions (77%) in eight of 10 patients (80%). The only patients whose tumors were not imaged on ¹⁸F-FDG PET/CT were two SDHB patients with solitary, biochemically silent tumors. Interestingly, the single SDHB patient whose neck tumors were ¹⁸F-FDG avid had a noradrenergic and dopaminergic biochemical profile and metastatic disease. In comparison, one SDHD patient (patient 1) presented with a biochemically silent solitary carotid body tumor that showed an uptake with ¹⁸F-FDG. The efficacy of ¹⁸F-FDG PET/CT in localizing these tumors should be noted, and, in the absence of ¹⁸F-FDOPA PET, the functional imaging of SDHx-related head and neck paragangliomas should be performed using ¹⁸F-FDG PET/CT.

¹¹¹In-pentetreotide scintigraphy is used as an imaging modality for pheochromocytomas/paragangliomas because of the presence of somatostatin receptors on these tumor cells, 73% of pheochromocytomas and 93% of paragangliomas (24). This radiopharmaceutical has demonstrated limited efficacy in primary pheochromocytomas/paragangliomas (31, 32); it has proven more useful in metastatic disease (33) and has high sensitivity in head and neck neuroendocrine tumors (34, 35). Kwekkeboom et al. (36) evaluated 25 patients with head and/or neck paraganglioma and reported a sensitivity of 94% (on a per lesion basis) for ¹¹¹In-pentetreotide scintigraphy. Similarly, a study by Koopmans et al. (7) demonstrated 93% sensitivity (on a per patient basis) with ¹¹¹In-pentetreotide scintigraphy in 29 patients with head and neck paragangliomas. In contrast, in the present series, ¹¹¹In-pentetreotide scintigraphy detected 16 of 25 (64%) of lesions in seven of nine patients (78%).

¹⁸F-FDA PET/CT is an excellent imaging modality for the diagnosis and localization of primary and metastatic pheochromocytomas/paragangliomas derived from the sympathetic nervous system (15, 32). In contrast, its sensitivity for head and neck paragangliomas, which are derived from the parasympathetic nervous system, was only 46% in our small series and localized only 12 of 26 (46%) lesions in four of 10 patients (40%).

Historically, ^123/131I-MIBG scintigraphy has been the staple functional imaging modality for the localization and diagnosis of pheochromocytomas/paragangliomas, but recent studies have demonstrated that other imaging techniques are superior (6, 15). Milardovic et al. (37) described ¹²³I-MIBG scintigraphy in 117 pheochromocytoma/paraganglioma patients and found low efficacy in imaging head and/or neck lesions with ¹²³I-MIBG scintigraphy localizing only 32 of 145 head and/or neck tumors. Bhatia et al. (11) also described ¹²³I-MIBG scintigraphy in head and neck paragangliomas and reported localization of eight of 14 carotid body tumors. We also found that ¹²³I-MIBG scintigraphy has little efficacy in these tumors, localizing only eight of 26 (31%) of the tumors in four of 10 patients (40%).

In the present study, we found that ¹⁸F-FDOPA PET imaging was most sensitive for very small tumors. Its low uptake in the brain and salivary glands was also a plus when compared with ¹⁸F-FDG PET/CT and ^123/131I-MIBG scintigraphy, particularly for small tumors located adjacent to these structures. The authors are aware of the positivity of ¹⁸F-FDOPA PET in other central nervous system tumors, such as glioblastomas, but these tumors are not located in the neck or the jugular fossa, and thus, we believe that ¹⁸F-FDOPA PET positivity in the head and neck region in our patient sample represent true paragangliomas.

In this study, all definite head and neck foci localized with functional imaging modalities were presumed to be true positive paragangliomas. We were comfortable using this as our gold standard in this series for several reasons. First, one of the primary advantages of functional imaging is its specificity compared with that of anatomic imaging, which is nonspecific and yet has often been used as a gold standard. More importantly, however, most lesions were also confirmed by at least one other functional imaging study, and 22 of 26 were confirmed on CT/MRI (one was confirmed retrospectively), the commonly used but nonspecific gold standard in many imaging studies when histologic confirmation is not obtained. Only three of 26 lesions were seen with a single modality (¹⁸F-FDOPA PET). Given the typical location of these lesions for paraganglioma and the fact that no false-positive ¹⁸F-FDOPA PET results were seen in any of the other patients, we feel confident that these foci represent true positive findings.

This study suggests that there are imaging differences between head and neck paragangliomas and other pheochromocytomas/paragangliomas as well as between genotypes. These differences may be due to differing cellular receptors and transporters between the parasympathetic and sympathetic ganglia. For example, vesicular monoamine transporter expression may be dependent on cell origin, with adrenal chromaffin cells mainly expressing vesicular monoamine transporter-1, whereas cells of the nervous ganglia tend to express high levels of vesicular monoamine transporter-2 (38, 39). Such differences and those that may be due to biochemical phenotype and tumor location remain to be fully explored in larger numbers of patients. Major limitations of this study are its small size and the lack of patients with sporadic and SDHC-related head and neck paragangliomas.

Conclusion

We show that such differences can influence the choice of functional imaging studies performed and suggest ¹⁸F-FDOPA PET as the first-line imaging agent for the localization and diagnosis of head and neck paragangliomas in SDHx-mutation carriers, regardless of biochemical phenotype. Although not widely available at present, with the advent of PET imaging and the more widespread use of it for diagnostic purposes, we can only assume that more and more facilities will aim to make studies such as ¹⁸F-FDOPA PET more widely available to patients. In the absence of ¹⁸F-FDOPA PET, we recommend the use of the more readily available ¹⁸F-FDG PET/CT or ¹¹¹In-pentetreotide scintigraphy in combination with CT/MRI for proper anatomical localization.