Original Paper Neuroendocrinology 2015;101:321–330 DOI: 10.1159/000381458

Received: October 13, 2014 Accepted after revision: March 4, 2015 Published online: March 13, 2015

Usefulness of Somatostatin Receptor Scintigraphy (99mTc-[HYNIC, Tyr3]-Octreotide) and 123I-Metaiodobenzylguanidine Scintigraphy in Patients with SDHx Gene-Related Pheochromocytomas and Paragangliomas Detected by Computed Tomography Ilona Michałowska a Jarosław B. Ćwikła l Mariola Pęczkowska b Mariusz I. Furmanek e John R. Buscombe p Wojciech Michalski f Aleksander Prejbisz b Małgorzata Szperl d Angelica Malinoc q Dariusz Moczulski m Zbigniew Szutkowski g Andrzej Kawecki g Jolanta Antoniewicz j Piotr Pęczkowski h Anna Lewczuk n Maciej Otto k Andrzej Cichocki i Grażyna Bednarek-Tupikowska o Marek Kabat b Hanna Janaszek-Sitkowska b Katarzyna Przybyłowska b Jadwiga Janas c Hartmut P.H. Neumann q Andrzej Januszewicz b Departments of a Radiology, b Hypertension and c Clinical Biochemistry, and d Laboratory of Molecular Biology, Institute of Cardiology, e Radiology and Diagnostic Imaging, Medical Center for Postgraduate Education, f Bioinformatics and Biostatistics Unit and Departments of g Head and Neck Cancer, h Urooncology and i Oncological Surgery, Maria Skłodowska-Curie Memorial Cancer Centre and Institute of Oncology, j Department of Nephrology and Arterial Hypertension, The Children’s Memorial Health Institute, and k Department of General, Vascular and Transplantation Surgery, Medical University of Warsaw, Warsaw, l Department of Nuclear Medicine, Faculty of Medical Science, University of Varmia and Masuria, Olsztyn, m Department of Internal Medicine and Nephrodiabetology, Medical University of Łódź, Łódź, n Department of Endocrinology and Internal Medicine, Medical University of Gdańsk, Gdańsk, and o Department of Endocrinology, Diabetology and Isotope Treatment, Wroclaw Medical University, Wrocław, Poland; p Department of Nuclear Medicine, Addenbrooke’s Hospital, Cambridge, UK; q Preventive Medicine Unit, Department of Nephrology and Hypertension, Albert Ludwigs University, Freiburg, Germany

Abstract Aims: The aim of this study was to assess the usefulness of somatostatin receptor scintigraphy (SRS) using 99mTc-[HYNIC, Tyr3]-octreotide (TOC) and 123I-metaiodobenzylguanidine

© 2015 S. Karger AG, Basel 0028–3835/15/1014–0321$39.50/0 E-Mail [email protected] www.karger.com/nen

(mIBG) in patients with SDHx-related syndromes in which paragangliomas were detected by computed tomography and to establish an optimal imaging diagnostic algorithm in SDHx mutation carriers. Methods: All carriers with clinical and radiological findings suggesting paragangliomas were screened by SRS and 123I-mIBG. Lesions were classified by body regions, i.e. head and neck, chest, abdomen with pelvis and adrenal gland as well as metastasis. Results: We evaluated 46 SDHx gene mutation carriers (32 index cases and 14 relatives; 28 SDHD, 16 SDHB and 2 SDHC). In this group, 102 benign tumors were found in 39 studied patients, and malig-

Mariola Pęczkowska Department of Hypertension, Institute of Cardiology Alpejska 42 PL–04-628 Warsaw (Poland) E-Mail mpeczkowska @ ikard.pl

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Key Words Somatostatin receptor scintigraphy · Metaiodobenzylguanidine · Computed tomography · Paraganglioma-pheochromocytoma syndromes · SDHx gene mutations

Introduction

Several distinct familial pheochromocytoma/paraganglioma (PPGL) syndromes are caused by mutations in gene-encoding subunits of succinate dehydrogenase (SDHx) itself or factors necessary for the correct assembly of the SDH complex [1–4]. The most common PPGL syndromes are those associated with mutations in the SDHB, SDHC and SDHD genes [2]. These syndromes are characterized by multifocal tumors, often located in different anatomical regions. Precise detection and localization of all lesions are vital for planning surgery, radionuclide therapy or radiotherapy. Computed tomography (CT) and magnetic resonance imaging (MRI) are the most commonly used anatomic imaging modalities to locate PPGLs (sensitivity of 77–98 and 90–100%, specificity of 29–92 and 50–100%, respectively) [5, 6]. Functional imaging is complementary to anatomical imaging because it provides a functional characterization of the tumors. It enables whole-body exploration and, thus, a more comprehensive localization and is particularly useful for the evaluation of multifocality, metastatic or recurrent disease. Moreover, some PPGLs that are missed in anatomical imaging due to their small size, unusual location, presence of surgical clips or postoperative changes can be detected by functional imaging. Specific radionuclide-based approaches have been developed in the diagnosis of PPGLs. One of these is based on metaiodobenzylguanidine (mIBG) and the other on somatostatin receptor radioligands (somatostatin receptor scintigraphy; SRS). The diagnostic yield of SRS and mIBG 322

Neuroendocrinology 2015;101:321–330 DOI: 10.1159/000381458

for the visualization of PPGLs has been determined in several studies, but there are still a limited number of prospective studies regarding SDHx mutation carriers [7–10]. The combination of anatomical and functional imaging procedures is often required to fully outline the tumor sites and the extent of the disease. Therefore, the aim of this study was to assess the usefulness of performing SRS using 99mTc-[HYNIC, Tyr3]-octreotide (TOC) and 123ImIBG in patients with SDHx-related syndromes in which PGLs were detected by CT and to establish an optimal diagnostic algorithm in SDHx mutation carriers.

Materials and Methods Our prospective single-institution open-labeled study is based on the Polish Pheochromocytoma-Paraganglioma Registry. Tumors were classified as pheochromocytomas of the adrenal gland or as extraadrenal abdominal, thoracic or head and neck PGLs (HNPs). These were the four designated tumor sites used for statistical analysis. Metastases in nonparaganglial tissues were the criterion for malignancy. Analyses for germline mutations included the following genes: RET (exons 10, 11, 13 and 16), VHL, NF1, SDHB, SDHD, SDHC, MAX, TMEM127 and SDHAF2 (all exons and test for large deletions/rearrangements) [1, 2, 11]. The Registry offered relatives of all index cases with revealed pathogenic mutation testing for the presence of mutations. Carriers of SDHx germline mutations (both index cases and their relatives) were prospectively investigated by the screening program, which included CT of the skull base and neck, the thorax and the abdomen, including the pelvis, and daily urinary excretion of total metanephrines. Metanephrine concentrations were measured using a Metanephrine Column Test kit (BioRad, Germany). All carriers of the SDHx gene mutations with clinical and radiological findings in CT suggesting paraganglial tumors were subsequently screened by SRS (TOC) and 123I-mIBG scintigraphy as additional functional imaging modalities. Exclusion criteria were refusal or inability to understand and sign informed consent and being a pregnant and/or lactating woman. A total of 350 patients [210 females (60%) and 140 males (40%); age range 7–86 years; mean age 44 ± 15 years] with symptomatic PGL and pheochromocytoma were enrolled in the study. We identified 102 patients with deleterious germline mutations (29%): 32 had RET mutations, 13 had VHL mutations, 30 had SDHD mutations, 3 had SDHC mutations, 14 had SDHB mutations, 1 had MAX mutations and 1 had TMEM 127 mutations; 6 patients had clinical signs of neurofibromatosis type 1 proven by genetic testing. Large deletions in the SDHB gene were detected in 2 patients. In total, 47 index cases were SDHx gene mutation carriers. Among 110 living first-degree relatives, 92 had been genetically tested; 53 of these were carriers and 36 of them agreed to be screened for paraganglial tumors. There were 17 relatives with SDHB mutations, 18 with SDHD mutations and 1 with an SDHC mutation. Among them, we identified 20 individuals with paraganglial tumors by CT (57%): 7 patients with SDHB (mean age 39 ± 11 years; 6 males, 1 female), 12 patients with SDHD (mean age

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nant disease was diagnosed in 7 patients. In benign tumors, the sensitivity of SRS was estimated at 77% and of 123I-mIBG at 22.0%. The SRS and mIBG sensitivity was found to be clearly region dependent (p < 0.001). The highest SRS sensitivity was found in head and neck paragangliomas (HNP; 91.4%) and the lowest was found in abdominal paragangliomas and pheochromocytomas (40 and 42.9%, respectively). The highest 123I-mIBG sensitivity was found in pheochromocytomas (sensitivity of 100%) and the lowest in HNP (sensitivity of 3.7%). In metastatic disease, SRS was superior to mIBG (sensitivity of 95.2 vs. 23.8%, respectively). Conclusion: SRS and 123I-mIBG single photon emission computed tomography (SPECT) sensitivity in SDHx patients is highly body region dependent. In malignant tumors, SRS is superior to 123I-mIBG SPECT. © 2015 S. Karger AG, Basel

Image Analysis CT examinations were blindly analyzed by two radiologists; SRS and 123I-mIBG images were independently read by two nuclear medicine experts. Tomographic images and functional images, as well as clinical data and hormonal status, were available for the readers in all cases. PPGLs detected by CT were correlated with functional imaging SRS and mIBG using image fusion in each case. The consensus status for the diagnosis or exclusion of PGLs or pheochromocytomas was confirmed by an expert committee. The basis for the sensitivity calculation was a consensus among the group of experts (‘gold standard’). The specificity of these three methods could not be calculated because the research included only patients with suspicion of tumors on CT examination. Structural and Functional Imaging Approaches Used in This Study Computed Tomography CT examinations were performed using dual-source CT (Somatom Definition, Siemens, Germany) after i.v. contrast administration. The chest, abdomen and pelvis were scanned during one examination, and the head and neck were scanned during another examination performed a few days later. The chest, abdomen and pelvis were examined after i.v. administration of 80–100 ml (depending on patient size) of a nonionic contrast material (Ultravist 370, Bayer Schering Pharma, Germany) using a power injector with a rate of 4–5 ml/s during the arterial phase (30 s). The head and neck CT examination started 40 s after the contrast medium injection because of the need to have information about arterial and venous vessels. The slice thickness was 1 mm, the tube voltage was set to 80– 120 kV and the tube current was 165–210 mA, depending on the regions scanned and the body size. The scanning parameters were adapted to the patient’s size and weight according to the ALARA (As Low As Reasonably Achievable). Any well-defined soft-tissue mass with typical intense enhancement after i.v. contrast administration was recognized as a PPGL. Somatostatin Receptor Scintigraphy SRS was performed in each case using TOC 99mTc-[TOC] (600– 700 MBq; Tektrotyd, National Center for Nuclear Research – Polatom, Poland). The detailed method of kit labeling with 99mTc was presented earlier [7]. Images were acquired between 1 and 3 h after the i.v. injection of a radiotracer using a double-head camera (Siemens, USA). The acquisition of head, neck, chest, abdominal and pelvis images was performed using the whole-body single photon emission computed tomography (SPECT) method. A low-energy high-resolution (LEHR) parallel-hole collimator with a single photo-peak window (140 keV ±15%) was used in each case. Routinely, we used 64 projections (a 128 × 128 matrix), 24 s per projection with no zoom. Reconstruction algorithms were based on commercially available iterative reconstruction software, i.e. OSEM (3D flash), including 16 subsets and 30 iterations with a standard Gaussian filter (3D flash; e-soft Workstation version 6.5, Siemens, USA).

SRS and mIBG in SDH-Related Paragangliomas

123I-Metaiodobenzylguanidine

A 123I-mIBG (AdreView, GE Healthcare, USA) study was performed in 44 patients. In each case, after thyroid suppression using Lugol’s solution, 1 day before the study, patients received an injection of 300–370 MBq of 123I-mIBG. Images were acquired between 12 and 24 h after the i.v. injection of the radiotracer using a doublehead camera (e-cam, Siemens, USA). The acquisition of head, neck, chest, abdominal and pelvis images was performed using the same method as with SRS – whole-body SPECT. A LEHR parallelhole collimator with a single photo-peak window (159 keV ±15%) was used. Routinely, we used 64 projections (128 × 128 matrix), 24 s per projection with no zoom. Reconstruction algorithms were based on commercially available iterative reconstruction software, i.e. OSEM (3D flash), including 8 subsets and 8 iterations with a standard Gaussian filter (3D flash; e-soft Workstation version 6.5, Siemens, USA). As with SRS, any focal or diffuse nonphysiological accumulation observed during the examination was reported as pathological. Diffuse low-activity intestinal uptake (with SRS) or liver and heart (with mIBG) were rated as nonspecific, physiologic uptake. Lesions were classified by body regions, i.e. head and neck, chest, abdomen with pelvis and adrenal gland as well as metastasis. Statistics Results are given as means with 95% confidence intervals (CIs), unless stated otherwise. To compare the sensitivities of a particular imaging modality between subgroups of patients, that is, to perform a comparison of independent observations, a Fisher exact test was used. A two-sided p < 0.05 was considered to be statistically significant. Statistical analysis was performed using IBM SPSS 20 for Linux (IBM SPSS Inc., Chicago, Ill., USA).

Results

We analyzed 46 SDHx gene mutation carriers (32 index cases and 14 relatives; 28 patients with SDHD, 16 patients with SDHB and 2 patients with SDHC) who underwent the entire research program. The mean age was 39 years, the age range was 18–73 years and there were 29 males and 17 females. Only the index cases were symptomatic on presentation; all relatives were asymptomatic. Data were analyzed separately for patients with benign and metastatic disease. Benign Tumors According to the accepted criterion, we classified tumors as benign when we did not find metastases in nonparaganglial tissues in anatomical imaging. There were 39 patients (23 males and 16 females, 25 patients with SDHD, 12 with SDHB and 2 with SDHC), the mean age was 40.2 ± 12.9 years and the mean follow-up time was 81.3 ± 55.9 months. According to the final expert consensus, 102 benign tumors were detected. There were 66 head and neck, 8 chest Neuroendocrinology 2015;101:321–330 DOI: 10.1159/000381458

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42 ± 14 years; 7 males, 5 females) and 1 with SDHC (a 73-year-old female). Six of them refused further investigations. Finally, we included 46 SDHx gene mutation carriers (32 index cases, 14 relatives; 28 patients with SDHD, 16 patients with SDHB, 2 patients with SDHC).

Malignant Tumors Seven patients were diagnosed with malignant disease with metastasis to bones, liver, lung and lymph nodes. There were 4 patients with SDHB gene mutations and 3 patients with an SDHD p.C11X mutation (5 male and 2 female). The mean age on presentation was 31.3 ± 5.9 years. The mean follow-up time was 102 ± 67 months; 1 patient died. In 3 patients, the primary tumor was located in the head and neck region, in 2 patients it was located extraadrenally in the retroperitoneal space, in 1 patient it was located in the urinary bladder and in 1 patient it was located in the chest. Clinical characteristics of these patients are presented in table 4. mIBG was negative in all patients, except for 1 with an SDHB gene mutation; SRS was positive in all patients, except for 1 SDHD mutation carrier with a solitary lesion in the liver. The sensitivity for SRS was estimated at 95.2% (95% CI 86.1–100), and for mIBG, it was estimated at 23.8% (95% CI 5.6–42.0). SRS sensitivity was found to be higher in malignant disease (95.2%), when compared with benign tumors (77.0%), but the difference was not statistically significant (p = 0.058). mIBG sensitivity was similar in benign and 324

Neuroendocrinology 2015;101:321–330 DOI: 10.1159/000381458

Table 1. Sensitivity of the screening methods in benign tumors

tested in the study in relation to the body region Region

mIBG sensitivity, % (95% CI)

SRS sensitivity, % (95% CI)

All PGL HNP Chest Abdomen Pheochromocytoma

22 (13.0 – 31.0) 3.7 (0 – 8.7) 0 64.3 (39.2 – 89.4) 100

77 (68.2 – 85.8) 91.4 (84.2 – 98.6) 71.4 (37.9 – 100.0) 40.0 (15.2 – 64.7) 42.9 (6.2 – 79.6)

malignant disease and was low (22.0 and 23.8%, respectively; not significant). The combined sensitivity of both functional methods was 88.5% (95% CI 81.8–95.2) for benign disease and 95.2% (95% CI 86.1–100) for malignant disease (not significant; table 5).

Discussion

To our knowledge, our series of SDHx mutation carriers, recruited prospectively, is the largest published cohort of SDHx subjects treated and diagnosed in one center who all underwent the same imaging exams analyzed by the same group of experts. PPGLs related to SDHx gene mutations are often multifocal and localized in different anatomical regions, so genetically predisposed patients required multiple investigations and multidisciplinary management. The tricarboxylic acid, or Krebs, cycle is central to the cellular metabolism of sugars, lipids and amino acids. Over the past decade, mutations in the Krebs cycle enzymes succinate dehydrogenase, fumarate hydratase and isocitrate dehydrogenase have been documented to be causally involved in carcinogenesis. Mutations in its subunits SDHA, SDHB, SDHC and SDHD, and in the assembly factor SDHAF2, result in syndromes with distinct tumor types, including PPGL, renal cell carcinoma, gastrointestinal stromal tumor, pituitary adenoma, thyroid carcinoma, neuroblastoma and, less often, other neoplasms. The most common PPGL syndromes are those associated with mutations in SDHD, SDHB and SDHC genes and are named PGL1, PGL4 and PGL3, respectively. These PPGL syndromes have characteristic features. In PGL1, most patients develop multiple HNPs, but other extraadrenal and adrenal tumors have been observed as well. Most SDHB-associated tumors (PGL4) are extraadrenal, occurring in the abdomen and pelvis, although they can be Michałowska  et al.  

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and 20 extraadrenal abdominal PGLs as well as 8 adrenal pheochromocytomas in the group with benign disease. Sixty-four tumors were surgically removed; 63 PPGLs were confirmed in histopathological examinations. SRS detected 87 out of 102 benign lesions (sensitivity 77%; 95% CI 68.2–85.8), 123I-mIBG detected 23 out of 102 lesions (sensitivity 22.0%; 95% CI 13.0–31.0). The SRS and mIBG sensitivity was clearly region dependent (p < 0.001). The highest SRS sensitivity was noted in HNPs (91.4%; 95% CI 84.2–98.6) and the lowest in abdominal PGLs and adrenal pheochromocytomas (40%; 95% CI 15.2–64.7 and 42.9%; 95% CI 6.2–79.6, respectively). The highest 123I-mIBG sensitivity was observed in adrenal pheochromocytomas (sensitivity 100%); the lowest was found when lesions were located in the head or neck (sensitivity 3.7%; table 1). When sensitivity was stratified by lesion localization, SRS sensitivity was significantly superior to that of 123ImIBG in HNPs and chest tumors (p < 0.001 and p < 0.05, respectively). It should be emphasized that despite there being no significant difference, all adrenal pheochromocytomas were detected with 123I-mIBG scintigraphy (sensitivity 100%), whereas SRS sensitivity in pheochromocytoma was only 42.6% (p = 0.076; table 2). The clinical characteristics of patients with benign tumors are presented in table 3.

Table 2. Comparison of SRS and mIBG scintigraphy sensitivity in benign tumors according to the body region

SRS mIBG p

HNP, % (95% CI)

Chest, % (95% CI)

Abdomen, % (95% CI)

PHEO, % (95% CI)

91.4 (84.2 – 98.6) 3.7 (0 – 8.7) A, p.C11X exon 1, c.33C>A, p.C11X exon 1, c.33C>A, p.C11X exon 1, c.33C>A, p.C11X exon 3, c.274G>T, p.D92Y exon 1, c.33C>A, p.C11X exon 1, c.33C>A, p.C11X exon 1, c.33C>A, p.C11X exon 1, c.33C>A, p.C11X exon 1, c.33C>A, p.C11X exon 1, c.33C>A, p.C11X exon 1, c.33C>A, p.C11X exon 1, c.33C>A, p.C11X exon 1, c.33C>A, p.C11X exon 1, c.33C>A, p.C11X exon 3, c.274G>T, p.D92Y exon 1, c.33C>A, p.C11X exon 1, c.33C>A, p.C11X exon 1, c.33C>A, p.C11X exon 1, c.33C>A, p.C11X exon 1, c.33C>A, p.C11X exon 1, c.33C>A, p.C11X exon 2, c.112C>T, p.R38X exon 1, c.33C>A, p.C11X exon 6, c.587G>A, p.C196Y exon 7, c.713_716delTCTC, p.Ser239TyrfsX8 exon 5, c.530G>A, p.R177H exon 7, c.650G>T, p.R217L exon 5, c.530G>A, p.R177H exon 5, c.530G>A, p.R177H exon 5, c.530G>A, p.R177H exon 5, c.530G>A, p.R177H exon 6, c.587G>A, p.C196Y exon 7, c.650G>T, p.R217L exon 5, c.530G>A, p.R177H exon 6, c.574T>C, p.C192R exon 3, c.78-2A>G, p.splicesite alteration exon 4, c.214C>T, p.R72C

missense

HNP

Hypersecretion of metanephrines in urine

yes yes yes n.d. yes yes n.d. yes

yes yes yes yes yes yes yes yes

yes

yes

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PHEO = Pheochromocytoma; FP = false positive in CT; n.d. = not done.

Table 4. Clinical characteristics of patients with a malignant disease Pa- Gene tient No.

Mutation type

Gender

Age at presentation, years

Follow- Surup, vival months

Primary tumor

mIBG

SRS

Metastases

liver, lungs, yes bones

Hypersecretion of metanephrines in urine

1

SDHD exon 1, c.33C>A, p.C11X, nonsense

female

39

132

alive

HNP

negative

positive

2

SDHD exon 1, c.33C>A, p.C11X, nonsense

female

36

192

alive

extraadrenal, abdomen

negative

negative liver

yes

3

SDHD exon 1, c.33C>A, p.C11X, nonsense

male

51

140

alive

HNP

negative

positive

bones

no

4

SDHB exon 1 deletion, large deletion

male

30

24

dead

urinary bladder positive

positive

liver, lungs, n.d. bones

5

SDHB exon 3, c.268C>T, p.R90X, nonsense

male

30

60

alive

extraadrenal, abdomen

negative

positive

liver, lungs, yes bones

6

SDHB exon 6, c.708T>C (int. 574 T>C), p.C192R, missense

male

22

48

alive

extraadrenal, chest

negative

positive

liver, lungs, yes bones

7

SDHB exon 7, c.689G>T, p.R230L, missense male

31

154

alive

HNP

negative

positive

bones

no

n.d. = Not done.

malignant and benign tumors Sensitivity, % (95% CI)

SRS mIBG SRS and mIBG

benign

malignant

77.0 (68.2– 85.8) 22.0 (13.0 – 31.0) 88.5 (81.8 – 95.2)

95.2 (86.1 – 100) 23.8 (5.6 – 42.0) 95.2 (86.1 – 100)

p

0.058 n.s. n.s.

n.s. = Nonsignificant.

found in any location, including the adrenal gland and the head and neck. It should be emphasized that SDHB mutation-associated tumors carry a substantial risk of malignancy, which has been estimated at 31–71%. Mutations in SDHC are less common compared to those in SDHD and SDHB. Patients with SDHC mutations tend to have solitary HNP, but rare extraadrenal paragangliomas and even pheochromocytomas have been described [12]. The mutations and variants identified in SDHx genes all over the world are collected in a mutation database hosted by the Leyden Open Variation Database (LOVD database), available from the following website: http://chromium.liacs.nl/lovd_sdh [13]. The challenge for clinical consensus conferences for relatively unusual disorders, such as PGL syndromes, is 326

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to reach a consensus regarding the adequate clinical management of these patients based on objective evidence. Two major challenges for consensus management guidelines for PPGL syndromes include surveillance techniques and important regions/locations for surveillance. CT and/or MRI are widely used in the diagnosis of patients with PPGLs. They usually offer high sensitivity but commonly detect adrenal nonchromaffin tumors as well as extraadrenal false-positive lesions. Functional imaging, however, offers high specificity but usually not the detailed anatomical information required for planning surgery [14–16]. We tested TOC [99mTc-TOC] SRS and 123I-mIBG, both functional approaches in the diagnosis of PPGL, because they have been licensed for clinical use in neuroendocrine neoplasms in Poland. Furthermore, SRS using [99mTc-TOC] showed a greater tumor to nontumor ratio and greater uptake than standard 111In-pentetreotide (OctreoscanTM) [7, 17]. A further advantage of 99mTc-TOC is also that it is a single-day procedure with an optimal acquisition time between 3 and 4 h after injection, which is more convenient for patients and imaging staff than the standard two-day protocol using 111In-pentetreotide and can be performed at a lower cost. We showed that the usefulness of 123I-mIBG and SRS using 99mTc-labeled somatostatin analogues for PPGL Michałowska  et al.  

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Table 5. Comparison of SRS and mIBG scintigraphy sensitivity in

a

b

c

d

detection in benign disease precisely depends on the anatomical region. SRS provided high sensitivity for HNP and chest PPGLs and was clearly superior to 123I-mIBG scintigraphy (p < 0.001 and p < 0.05, respectively), whereas mIBG seems to be more sensitive than SRS in subdiaphragmal tumors. Although in our study the overall mIBG sensitivity in benign PPGLs was low (22%), this method seems to be of value in the assessment of the functional status of adrenal tumors with 100% sensitivity. Other studies that have included a high number of extraadrenal, multiple or hereditary PPGLs have also shown reduced 123I-mIBG sensitivity (40– 75%) and its region dependence [18–20]. The most likely explanation of such a low overall sensitivity of mIBG in our study is a high incidence of HNPs, especially in SDHD gene mutation carriers, where the usefulness of mIBG is limited. SRS sensitivity was significantly higher than mIBG in malignant disease (95.2 vs. 23.8%, respectively). Malig-

nant PPGLs may undergo tumor dedifferentiation, with a loss of specific neurotransmitter transporters. The result is an inability to accumulate mIBG and a consequent lack of localization, that is, decreased sensitivity in 123ImIBG imaging. Previous studies concerning malignant PPGLs pointed out the need to screen for SDHB mutations, especially in patients with metastatic disease, but also in those with nonmetastatic tumors with false-negative 123I-mIBG SPECT [18, 20]. This is important because it has been shown that SDHB mutations are independently associated with higher rates of malignancy and mortality (fig. 1a–d). We showed that SDHD mutation carriers with malignant disease may also yield the same false-negative mIBG SPECT results, which suggests a similar biology of the tumors. All of our SDHD patients harbor an SDHD p.C11X truncating mutation [21], which may be associated with a fast growth rate and a higher risk of malignant transformation. We therefore suggest that patients with

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Fig. 1. A 35-year-old male patient with a confirmed SDHB mutation, malignant PGL, currently nonresectable liver metastases, multiple lymph node involvement and previous splenectomy. a, b CT after i.v. contrast enhancement; transverse (a) and coronal (b) view of the abdomen; liver metastases and massive abdominal lymph node involvement. c, d Functional and structural image fusion using SRS 99mTc-TOC (Tektrotyd) and CT; transverse (c) and coronal (d) views of the abdomen.

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tive comparison between 68Ga-DOTATOC PET/CT and 18 F-DOPA PET/CT in patients with extraadrenal PPGL, Kroiss et al. [26] indicated that 68Ga-DOTATOC PET may be superior to 18F-DOPA PET and diagnostic CT in providing valuable information for pretherapeutic staging of extraadrenal PPGL, particularly in surgically inoperable tumors and metastatic or multifocal disease. The last study by Kroiss et al. [26], which included 10 patients with either metastatic HNP or multifocal extraadrenal PPGL, showed that on a per-lesion basis, the overall sensitivity of 68Ga-DOTATOC PET was 100% and that of 123 I-mIBG SPECT/CT was 6.9%. The authors concluded that 68Ga-DOTATOC PET/CT is superior to 123I-mIBG SPECT/CT, particularly in head and neck and bone lesions. Altogether, these recent data suggest that PET appears to be useful for PPGL diagnosis and seems to be superior to mIBG and SRS. On the other hand, the recently published results of a large multicenter study in SDHx mutation carriers by Gimenez-Roqueplo et al. [27] indicated that the best diagnostic performance was obtained by combining anatomical imaging tests and SRS with sensitivity on central assessment, estimated at 98.6%, which is comparable with PET. When we analyzed the data concerning PET and scintigraphy sensitivity, we could observe that all of these methods have some limitations. Specific PET tracer sensitivity seems to have the same region dependency as the radionuclides used for mIBG and SRS scintigraphies. A metaanalysis by Treglia et al. [24] showed that PET sensitivity can be comparable to combined anatomical and functional methods. The question is whether all patients with PPGLs need functional examinations, especially when CT and MRI are highly sensitive. The SDHx gene mutation carriers are group specific. Most of them have multifocal and multiple tumors, and the specificity of the anatomic examinations is rather low. This is the reason why we believe that in the case of multifocality, the functional characterization of the tumors might be of great clinical value. The guidelines published in 2014 for PPGL recommend the use of 123I-mIBG scintigraphy as a functional imaging method in patients with metastatic PGL detected by other imaging methods when radiotherapy using 131ImIBG is planned and, occasionally, in some patients with an increased risk of metastatic disease and points out that 18 F-FDG PET/CT is the preferred imaging method over 123 I-mIBG scintigraphy in patients with malignant disease [28]. Our study shows that there is a high sensitivity of SRS in metastatic PGLs in patients with SDHB and SDHD gene mutations and that SRS SPECT is superior to Michałowska  et al.  

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false-negative 123I-mIBG SPECT and malignant disease should be tested not only for SDHB mutations but also for SDHD and undergo a more regular clinical and imaging follow-up. It should be added that most of our SDHD patients harbor this type of mutation, which was identified as a founder mutation with a high rate of multiple HNP tumors, but also chest and abdominal extraadrenal tumors [21]. The rate of malignancy in the SDHD p.C11X mutation group was 14%. Recent data suggest that positron emission tomography (PET) appears to be more useful for PGL diagnosis than mIBG and SRS scintigraphies using 99mTc-labeled analogues and also 111In-Octreoscan [17, 18, 22]. A wide range of PET tracers have been proposed for imaging of paraganglial tumors. PET tracers include tracers that are specific to chromaffin tissue agents, such as [11C]-hydroxyephedrine, 6-[18F]-fluorodihydroxyphenylalanine ([18F]-FDOPA) and 6-[18F]-fluorodopamine as well as tracers specific to somatostatin receptor agents, such as [68Ga]-labeled somatostatin analogues and others that are nonspecific, such as [18F]-fluorodeoxyglucose ([18F]FDG PET), which is involved in glucose metabolism. Timmers et al. [23] in a large prospective study including 216 consecutive patients, 66 with SDHB and 12 with SDHD mutations, have shown that metastases are better detected by [18F]-FDG PET than by [123I]-mIBG SPECT with sensitivities of 80 and 49%, respectively, and are able to detect bone metastases better than whole-body CT and/or MRI (sensitivity 94 vs. 79%) and to confirm that the sensitivity of [18F]-FDG PET is higher in SDHB/Drelated than non-SDHB/D-related malignant PPGLs and pheochromocytomas. In another prospective study of 25 patients (2 SDHB and 6 SDHD mutation carriers), [18F]FDOPA PET was also shown to be better than [123I]mIBG scintigraphy (sensitivity 98 vs. 53%) in patients with benign extraadrenal, noradrenaline-producing, hereditary PPGL, especially SDHD related (sensitivity 96 vs. 40%) [8]. In a recent metaanalysis of 11 studies comprising 275 patients with suspected PPGL (31 patients with SDHB mutations), the pooled sensitivity of 18F-DOPA PET and PET/CT in detecting tumors was 91% in a perpatient-based analysis and 79% in a per-lesion-based analysis [24]. Pheochromocytomas routinely express somatostatin receptors (SSTRs), predominantly SSTR3 and to some extent SSTR2. In 2007, Win et al. [25] for the first time demonstrated the value of somatostatin receptor PET (PET SRS) imaging in malignant pheochromocytoma. Since then, several other peptides of [68Ga]-labeled somatostatin analogues have been proposed. In a recent retrospec-

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I-mIBG SPECT as well in this group of patients. Since peptide receptor radionuclide therapy is also an option for the treatment of malignant PPGL, we propose both functional methods (SRS and mIBG) in these patients [29]. It is also worthy to note that mIBG and SRS scintigraphies, which are performed in Poland using labeled 99m Tc analogues, are more easily available in any nuclear medicine department than highly specific PET radiotracers, and the combined sensitivity of these methods is comparable to PET. In conclusion, SRS using 99mTc-TOC and 123I-mIBG SPECT sensitivity in SDHx patients is highly body region dependent. In malignant tumors, SRS is superior to 123I-mIBG.

Acknowledgement This work was supported by a grant from the Institute of Cardiology, Warsaw (grant No. 2.44/VII/10).

Disclosure Statement All authors declare that there are no conflicts of interest that could be perceived as prejudicing the impartiality of the research reported.

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