Role of positron emission tomography and bone scintigraphy in the evaluation of bone involvement in metastatic pheochromocytoma and paraganglioma: specific implications for succinate dehydrogenase enzyme subunit B gene mutations

in Endocrine-Related Cancer
View More View Less
  • 1 Reproductive Biology and Medicine Branch, Nuclear Medicine Department, Clinical Neurocardiology Section, 3rd Department of Medicine, Department of Medicine, National Institutes of Child Health and Human Development

We performed a retrospective analysis of 71 subjects with metastatic pheochromocytoma and paraganglioma (30 subjects with mutation of succinate dehydrogenase enzyme subunit B (SDHB) gene and 41 subjects without SDHB mutation). Sixty-nine percent presented with bone metastases (SDHB +/−: 77% vs 63%), 39% with liver metastases (SDHB +/−: 27% vs 47%), and 32% with lung metastases (SDHB +/−: 37% vs 29%). The most common sites of bone involvement were thoracic spine (80%; SDHB+/−: 83% vs 77%), lumbar spine (78%; SDHB +/−: 78% vs 75%), and pelvic and sacral bones (78%; SDHB +/−: 91% vs 65%, P=0.04). Subjects with SDHB mutation also showed significantly higher involvement of long bones (SDHB +/−: 78% vs 30%, P=0.007) than those without the mutation. The best overall sensitivity in detecting bone metastases demonstrated positron emission tomography (PET) with 6-[18F]-fluorodopamine ([18F]-FDA; 90%), followed by bone scintigraphy (82%), computed tomography or magnetic resonance imaging (CT/MRI; 78%), 2-[18F]-fluoro-2-deoxy-d-glucose ([18F]-FDG) PET (76%), and scintigraphy with [123/131I]-metaiodobenzylguanidine (71%). In subjects with SDHB mutation, imaging modalities with best sensitivities for detecting bone metastases were CT/MRI (96%), bone scintigraphy (95%), and [18F]-FDG PET (92%). In subjects without SDHB mutations, the modality with the best sensitivity for bone metastases was [18F]-FDA PET (100%). In conclusion, bone scintigraphy should be used in the staging of patients with malignant pheochromocytoma and paraganglioma, particularly in patients with SDHB mutations. As for PET imaging, [18F]-FDG PET is highly recommended in SDHB mutation patients, whereas [18F]-FDA PET is recommended in patients without the mutation.

Abstract

We performed a retrospective analysis of 71 subjects with metastatic pheochromocytoma and paraganglioma (30 subjects with mutation of succinate dehydrogenase enzyme subunit B (SDHB) gene and 41 subjects without SDHB mutation). Sixty-nine percent presented with bone metastases (SDHB +/−: 77% vs 63%), 39% with liver metastases (SDHB +/−: 27% vs 47%), and 32% with lung metastases (SDHB +/−: 37% vs 29%). The most common sites of bone involvement were thoracic spine (80%; SDHB+/−: 83% vs 77%), lumbar spine (78%; SDHB +/−: 78% vs 75%), and pelvic and sacral bones (78%; SDHB +/−: 91% vs 65%, P=0.04). Subjects with SDHB mutation also showed significantly higher involvement of long bones (SDHB +/−: 78% vs 30%, P=0.007) than those without the mutation. The best overall sensitivity in detecting bone metastases demonstrated positron emission tomography (PET) with 6-[18F]-fluorodopamine ([18F]-FDA; 90%), followed by bone scintigraphy (82%), computed tomography or magnetic resonance imaging (CT/MRI; 78%), 2-[18F]-fluoro-2-deoxy-d-glucose ([18F]-FDG) PET (76%), and scintigraphy with [123/131I]-metaiodobenzylguanidine (71%). In subjects with SDHB mutation, imaging modalities with best sensitivities for detecting bone metastases were CT/MRI (96%), bone scintigraphy (95%), and [18F]-FDG PET (92%). In subjects without SDHB mutations, the modality with the best sensitivity for bone metastases was [18F]-FDA PET (100%). In conclusion, bone scintigraphy should be used in the staging of patients with malignant pheochromocytoma and paraganglioma, particularly in patients with SDHB mutations. As for PET imaging, [18F]-FDG PET is highly recommended in SDHB mutation patients, whereas [18F]-FDA PET is recommended in patients without the mutation.

Introduction

Pheochromocytomas (PHEO) are catecholamine-producing tumors arising from chromaffin cells of the adrenal medulla. Paragangliomas (PGL) are tumors arising either from extra-adrenal chromaffin cells, and can originate either from sympathetic nervous system-associated chromaffin tissue (mainly abdomen and pelvis, less frequently thorax), or parasympathetic-associated chromaffin tissue (head and neck). Sympathetic PGL are usually hormonally active and are called extra-adrenal PHEO. They occur less frequently than adrenal PHEO (Lenders et al. 2005).

PHEO are not only typically benign tumors but may also be malignant in 10–25% of cases, but this frequency increases significantly with PGL, where up to 50% may be malignant (O'Riordain et al. 1996, John et al. 1999, Lehnert et al. 2004, Zarnegar et al. 2006). Recently, it has been shown that the high prevalence of malignancy in subjects with PGL is linked mainly to mutations of the gene encoding the B subunit of the mitochondrial complex II enzyme succinate dehydrogenase enzyme subunit B (SDHB; Amar et al. 2005, Benn et al. 2006, Brouwers et al. 2006, Timmers et al. 2007).

The main sites of metastatic spread of malignant PHEO/PGL are lymphatic nodes (local or distant), bones, liver, and lungs (Yu & Pacak 2002, Lehnert et al. 2004). However, limited data have been published about the frequency of spread to each metastatic site. According to the literature (papers focused mainly on the natural history and effect of treatment in malignant PHEO/PGL), the most common sites of distant metastases are skeletal, but frequency varies from 37% to 77% (Averbuch et al. 1988, Schlumberger et al. 1992, Loh et al. 1997, Plouin et al. 1997, Vassilopoulou-Sellin 1998, Goldstein et al. 1999, Kimura et al. 2005, Fitzgerald et al. 2006). Furthermore, only two reports focused on metastatic bone disease in malignant PHEO/PGL. The first study was published in 1972 and described the roentgenologic appearance of bone metastases in ten subjects (James et al. 1972). The second publication from 1986 included 56 subjects with malignant PHEO/PGL and found a 68% prevalence of bone metastases, primarily located in ribs, spine, and pelvis (Lynn et al. 1986). In that study, a relatively low sensitivity was found using the specific functional imaging agent [131I]-metaiodobenzylguanidine ([131I]-MIBG) for detecting bone lesions compared with bone scintigraphy and computed tomography (CT; 51% vs 71% and 74%).

In the last two decades, much progress has been made in the development of improved functional imaging for PHEO/PGL and other neuroendocrine tumors, mainly due to the introduction of new radiopharmaceuticals specific for PHEO/PGL. These include specific functional imaging agents such as [123I]-MIBG, 6-[18F]-fluorodopamine ([18F]-FDA), [11C]-hydroxyephedrine, or [18F]-fluorodihydroxyphenylalanine (Eriksson et al. 2000, Hoegerle et al. 2002, Ilias et al. 2003, Pacak et al. 2004, Trampal et al. 2004, Franzius et al. 2006, Mann et al. 2006, Rufini et al. 2006, Sundin et al. 2007) as well as the non-specific functional agent 2-[18F]-fluoro-2-deoxy-d-glucose ([18F]-FDG; Shulkin et al. 1999, Mann et al. 2006).

In a retrospective analysis, we assessed the role of bone scintigraphy using Tc-99m-methylene diphosphonate, [123/131I]-MIBG scintigraphy, [18F]-FDA, and [18F]-FDG positron emission tomography (PET) scanning and CT and magnetic resonance imaging (MRI) in the detection of bone lesions in metastatic PHEO/PGL. Since many of the patients in this study were found to have SDHB mutations, our aim was also to find possible differences in the prevalence, location, and detection of bone metastases between patients with and without SDHB mutations.

Materials and methods

Patients

We retrospectively selected 65 subjects with malignant PHEO/PGL referred to the National Institutes of Health (NIH) and six subjects with malignant PHEO/PGL referred to the Third Department of Medicine, General Faculty Hospital, Prague, Czech Republic between November 2000 and May 2006 (Tables 1–3) from the database of subjects who had undergone complete genetic testing for mutations in SDHB and other PHEO/paraganglioma-related genes (rearranged during transfection (RET), von Hippel–Lindau syndrome (VHL), and SDHD). One NIH patient with multiple endocrine neoplasia type 2 was excluded from analysis because of coexistent metastatic medullary thyroid cancer. Malignancy was defined as the presence of chromaffin tissue at sites where no chromaffin tissue should be expected (Kimura et al. 2005) and was proven by biopsy in 49 subjects. In the remaining 22 subjects, metastatic PHEO/PGL was diagnosed by the presence of persistently elevated catecholamine/metanephrine levels, positive imaging studies and previous history of PHEO/PGL. Of these 71 patients, 30 had a mutation of the SDHB gene. Three others had mutation of the RET gene (patients nos 2 and 28 were siblings), three subjects had mutation of the VHL gene, and one subject had mutation of the SDHD gene (Tables 2 and 3). Genetic testing for mutation of the SDHB gene was performed at the Department of Human Genetics of the Pittsburgh University Medical Center as described elsewhere (Brouwers et al. 2006) and for mutations of the VHL, RET, and SDHD genes at Department of Genetics of the Children's Hospital of Philadelphia under a commercial research contract (patients from the NIH) and in the Institute of Biology and Medical Genetics of the First Faculty of Medicine in Prague. The study protocols were approved by the Institutional Review Board of the National Institutes of Child Health and Human Development at the NIH and by the ethics committee of the First Faculty of Medicine. All patients provided written informed consent.

Table 2

Characteristics of subjects with malignant pheochromocytoma and paraganglioma with succinate dehydrogenase enzyme subunit B (SDHB) mutation and sensitivities in detection of bone metastases

Sensitivity in detection of bone metastasis
No.SexAge at malignancy (years)Primary tumorSites of metastasesSymptoms related to bone (before diagnosis)BiochemistryCT/MRIBS[123/131I]-MIBG[18F]-FDA[18F]-FDG
Patients with bone involvement
 1aF38EAa/p, b, li0NE+DA1100
 2M19EAa/p, b, li, lu, ne0NE+DA11111
 3M20EABAbdominal painNE1101
 4M14EAa/p, b, lu0NE1100
 5F23EAa/p, bSkull lesion immediately after diagnosis NE11111
 6aM28EA (pelvic) + rib massa/p, b, lu, neRib fracture diagnosisNE+E+DA11111
 7aM8EA (parailiac)a/p, b0NE+DA1111
 8M43EAa/p, b, lu, me0NE+DA110
 9aM39EAa/p, b, meBack pain, L laminectomy011011
 10F43EAa/p, b, li0NE1111
 11aM35EA (aortic bifurcation)a/p, b, me0NE+DA1011
 12M31EAb001111
 13M60EA (aortic bifurcation)a/p, b, luPelvic pain011111
 14aM23EA (aortic bifurcation)a/p, b0NE+DA1111
 15aF24EAbAbdominal painNE11111
 16M50EA, neck PGLa/p, b, meAbdominal painDA1100
 17M48EAbHip painNE11111
 18F36EAa/p, b, li, luT2 laminectomy01111
 19M56EAa/p, b0NE1111
 20F72EA (aortic bifurcation)a/p, b0NE+E+DA11
 21M12EAa/p, b, luBack painNE1111
 22M35EAa/p, b, liBack pain, T4-T7 laminectomyNE+DA1001
 23F52EAb.li, lu0NE0010
Patients without bone involvement
 24F55RAa/p, me, neNE0Ribs (repeated examination normal)000
 25M27EA, neck PGLa/p, lu, meNE+DA0One lesion in tibia, post-therapeutic scan negative00
 26F38EA (pelvic)a/p, liNE+DA00000
 27F53EAa/p, li, lu, neNE+DA00000
 28aF45EA, neck PGLa/pNE000
 29F36EA (urinary bladder)a/p, meNE+DA0000
 30F36EA (pelvic)a/p, luNE000

CT/MRI, computed tomography or magnetic resonance imaging; BS, bone scintigraphy; [123/131I]-MIBG, [123I] or [131I]-metaiodobenzylguanidine scintigraphy; [18F]-FDA, [18F]-fluorodopamine positron emission tomography; [18F]-FDG, [18F]-fluorodeoxyglucose positron emission tomography; F, female; M, male; RA, right adrenal; EA, extra-adrenal (abdominal); PGL, paraganglioma; a/p, abdominal/pelvic; me, mediastinum; lu, lung; li, liver; b, bone; NE, norepinephrine (norepinephrine or normetanephrine secretion); E, epinephrine (epinephrine or metanephrine secretion); DA, dopamine; MEN, multiple endocrine neoplasia; VHL, von Hippel–Lindau syndrome.

Malignant at first presentation; 1, positive; and 0, negative.

Table 3

Characteristics of subjects with malignant pheochromocytoma and paraganglioma without succinate dehydrogenase enzyme subunit B (SDHB) mutation and sensitivities in detection of bone metastases

Sensitivity in detection of bone metastasis
No.SexAge at malignancy (years)Primary tumorSites of metastasesSymptoms related to the bone (before diagnosis)BiochemistryCommentsCT/MRIBS[123/131I]-MIBG[18F]-FDA[18F]-FDG
Patients with bone involvement
 1F20EA (presacral)a/p, b, liPain from primary lesionNE+DA1011
 2F38RA, LAli, b0NE+EMEN 2A (sister no. 28)1111
 3F45RAa/p, b, lu0NE0101
 4M56EAbPain in ribs and shoulder blade, Th5 laminectomyNE1111
 5F55EAb0NE+E00010
 6aF36EAa/p, b, me0NECarcinoid, polycythemia vera00010
 7F44LAa/p, b, li, 0NE00110
 8M23RA, neck PGLa/p, b.li, me0NESDHD01111
 9aF64EA (pelvic)a/p, bPolymyalgia rheumatica for 7 years before diagnosisNE11111
 10aM36EA, neck PGLa/p, b, luFirst presentation: meta in the left orbitNE111
 11M37RAa/p, b, lu0NE+E1111
 12M63LAa/p, b, li, lu0NE01110
 13M23EAa/p, bChest painNE11111
 14aM21EA (liver)b, li, luL1 laminectomy before evaluationNE00110
 15F42LAa/p, b, li, lu, me0NEPos. family history11011
 16F28RAa/p, b, li, lu0NE+E111
 17aF54RAa/p, b, li0NE+E0011
 18aF48LAb, li0NE0101
 19aF36RAa/p, b0NE+E111
 20aF55RAb, liHypercalcemiaNE111
 21aF59EAa/p, b, lu0NE+E1111
 22F67EAb, li, lu0NE+DA1111
 23M32EAb0NE1011
 24M29vs. EAa/p, b, li.0NE+E111
 25M44EAa/p, b, liBack painNE111
 26M53RAa/p, b, li0NE+DA11
Patients without bone involvement
 27F32LAa/pNE+EVHL00000
 28F39RA,LAa/pNEMEN 2A (sister no. 2)00000
 29F15Adrenal+kidneya/pNE00000
 30F48EAa/pNE00000
 31M30RA, LAa/pNEVHL0000
 32M64LAa/pNE+EVHL0000
 33M84LAa/p, li, luNE000
 34M32RA, LA, EAa/pNE000
 35M72RAa/p, liNE+E+DA000
 36aM22EA (bladder)a/pNE+E000
 37M41EAa/pNE00
 38aM38RAa/pNEMEN 2A00
 39aF28RAli, luNE+DA00
 40M50EAa/p, liNE00
 41M47EA (abdomen, bladder)a/p, li, luNE+DA0

CT/MRI, computed tomography or magnetic resonance imaging; BS, bone scintigraphy; [123/131I]-MIBG, [123I] or [131I]-metaiodobenzylguanidine scintigraphy; [18F]-FDA, [18F]-fluorodopamine positron emission tomography; [18F]-FDG, [18F]-fluorodeoxyglucose positron emission tomography; F, female; M, male; RA, right adrenal; LA, left adrenal; EA, extra-adrenal (abdominal); PGL, paraganglioma; a/p, abdominal/pelvic; me, mediastinum; lu, lung; li, liver; b, bone; NE, norepinephrine (norepinephrine or normetanephrine secretion); E, epinephrine (epinephrine or metanephrine secretion); DA, dopamine; MEN, multiple endocrine neoplasia; VHL, von Hippel–Lindau syndrome.

Malignant at first presentation; 1, positive; and 0, negative.

Biochemical analyses

In the NIH subjects, plasma catecholamines and metanephrines were measured by liquid chromatography with electrochemical detection as described elsewhere (Eisenhofer et al. 1986, Lenders et al. 1993). In subjects from the Czech Republic, urinary catecholamines were used for therapeutic decisions. These were measured by liquid chromatography with electrochemical detection. All elevations above the upper range of normal values were counted as positive. In most subjects, elevations were many times above upper reference limits, but patients with only mild elevations were also considered positive. Since all patients in the present study carried a known diagnosis of metastatic PHEO/PGL, clonidine suppression tests were not performed.

Imaging techniques

The vast majority of the imaging studies were performed at one of the two study centers, but on occasion, outside imaging studies (two [123I]-MIBG and two bone scans) were also used for the analysis.

CT and MRI from the neck to the pelvis were performed at the NIH using oral and i.v. contrast as described previously (Ilias et al. 2003, Mamede et al. 2006). In the Czech Republic, CT scans, but not MRI, were performed from thorax to pelvis, also using oral and i.v. contrast.

PET imaging was performed only at the NIH. For [18F]-FDA PET, patients fasted for at least 4 h and refrained from caffeine, tobacco, and alcohol for 12 h before i.v. injection of [18F]-FDA (1 mCi, 37 mBq). Before March 2005, [18F]-FDA PET scans were performed using an Advance scanner (General Electric Healthcare Technologies, Milwaukee, WI, USA). Eight-minute emission images were obtained in 2D mode from the mid-skull to the mid-thigh starting ∼3 min after tracer injection. Three-minute transmission scans were obtained for attenuation correction. Later, [18F]-FDA PET scans were done using a Discovery ST PET/CT scanner (General Electric Healthcare Technologies). Eight-minute emission images were obtained in 2D mode starting ∼5–10 min following injection.

FDG PET/CT studies were performed in patients beginning in March 2005. Patients fasted for at least 6 h prior to injection with 15 mCi, 555 mBq [18F]-FDG. Imaging was begun ∼60 min following injection from the mid-skull to the mid-thigh. Five-minute emission scans were obtained in 2D mode. CT studies for attenuation correction and anatomical co-registration were performed without contrast.

For [123/131I]-MIBG scanning, patients were imaged at ∼24 h (and in some cases also at 48 h) following i.v. administration of ∼10 mCi (370 MBq) [123I]-MIBG (56 subjects from the NIH and 6 from the Czech Republic) or 0.5 mCi (18.5 MBq) of [131I]-MIBG (seven subjects from the NIH). Both planar and single photon emission CT of the neck through pelvis were performed.

Bone imaging studies were performed ∼3 h following administration of ∼25 mCi (925 MBq) of Tc-99m-methylene diphosphonate.

Data analysis

Apart from [18F]-FDA PET, imaging studies were performed as routine procedures and interpreted by experienced specialists in radiology and nuclear medicine. Bone scans were considered positive for bone metastases only when multiple lesions (different from degenerative involvement) were found. If only one suspicious lesion was seen, confirmation by other imaging modalities was required (Krasnow et al. 1997, Hamaoka et al. 2004). [18F]-FDA PET studies were each read by two nuclear medicine physicians during separate reading sessions, blinded to other imaging results. Lesions were graded on a scale of 1–5 (1, not PHEO; 2, doubtful; 3, equivocal; 4, probable and 5, definite PHEO). Lesions with scores of 4 and 5 were counted as positive findings. Discrepancies were resolved by consensus review. For sensitivity comparisons, only contemporaneous studies performed within 3 months of each other were used.

Data are shown as mean±s.d. Variables in unpaired data were compared using either the unpaired t-test or Mann–Whitney test (in the case of non-parametrical data distribution). Categorical variables were assessed by the Fisher exact test. The sensitivity of each imaging method for detecting metastatic bone involvement (number of positive subjects per method/number of detected subjects by any method) was calculated for each group of subjects. For comparative sensitivity calculations, only regions covered by CT/MRI (neck to pelvis/upper femur) were used. Other regions (e.g. humerus, distal femur, or tibia) covered by whole-body bone and MIBG scintigraphy were used only for overall characterization of metastatic disease in SDHB-positive and -negative patients. Differences in sensitivities in each group of subjects (all subjects, subjects with and without SDHB mutation) were assessed by the McNemar test. P<0.05 values were considered as significant.

Results

In this retrospective analysis, the abdomen/pelvis was the most frequent site of metastases (80%), followed by bone (69%), liver (39%), and lung (32%; Table 1). Analysis of differences between subjects with and without SDHB mutation showed that primary extra-adrenal tumors were significantly more frequent in subjects with SDHB mutation (P<0.001, Table 1, and in each subject in Tables 2 and 3). These subjects also demonstrated biochemical phenotypes typical of less-differentiated tumors (positive dopamine or failure to secrete catecholamines) more frequently than those without SDHB mutation (P=0.001, Tables 1–3). However, no significant differences were found for age at which malignant disease was first diagnosed or in the frequency of metastatic lesions (bone, liver, and lungs), although subjects without SDHB mutation presented with non-significantly higher frequency of liver metastases. Subjects with SDHB mutation presented with a slightly higher frequency of bone-related complaints and surgery. Five subjects required spine surgery for extensive vertebral involvement (SDHB-positive patients nos 9, 18, and 22 in Table 2, SDHB-negative nos 4, 14 in Table 3) and one subject presented with malignant hypercalcemia (patient no. 20 in Table 3).

Table 1

Baseline characteristics and distribution of metastases in subjects with malignant pheochromocytoma and paraganglioma with regard to genetic testing

VariableAll subjectsn=71SDHB positiven=30SDHB negativen=41P
Gender (male/female)38/3317/1321/20NS
Primary tumor (adrenal/extra-adrenal)21/501/2920/21<0.001
Age at primary diagnosis (years)36±1634±1638±16NS
Interval to malignancy (years)4.4±6.23.4±5.95.2±6.2NS
Interval to bone metastasis (years)5.6±7.95.1±9.66.0±6.2NS
Biochemical patterns of less-differentiated tumors (positive dopamine or failure to secrete catecholamines; %, positive)34 (24)60 (18)15 (6)0.001
Metastatic locations (%, positive)
 Abdominal/pelvic80 (57)83 (25)78 (31)NS
 Bone69 (49)77 (23)63 (26)NS
 Liver39 (28)27 (8)49 (20)0.09
 Lung32 (23)37 (11)29 (12)NS
 Other (mediastinum and neck)20 (14)37 (11)7 (3)0.005
Location of bone involvement (%, positive)n=49n=23n=26
 Skull37 (18)30 (7)42 (11)NS
 Cervical spine39 (19)37 (8)50 (13)NS
 Thoracic spine80 (39)83 (19)77 (20)NS
 Lumbar spine78 (38)78 (18)75 (20)NS
 Pelvis and sacrum78 (38)91 (21)65 (17)0.04
 Long bones (femur, humerus, and tibia)53 (26)78 (18)30 (8)0.001
 Ribs61 (30)56 (13)65 (17)NS
 Other (sternum, scapula, clavicula, and hyoid)38 (19)43 (10)35 (9)NS
Symptoms from bone involvement39 (19)48 (11)31 (8)NS

NS, non-significant.

The most frequent sites of bone involvement were the thoracic (80%) and lumbar (78%) spine and the pelvis and sacrum (78%; Table 1). Other frequent sites of bone metastases were the ribs (61%) and long bones (femur, humerus, and tibia; 53%), followed by the cervical spine (39%) and skull (37%). The comparison of disease sites detected in subjects with and without SDHB mutation revealed a significantly higher frequency of metastatic involvement of long bones (78% vs 30%, P=0.001) and pelvis and sacrum (91% vs 65%, P=0.04; Table 1), but not in other locations in subjects with SDHB mutation.

Results of the various imaging modalities are presented in Table 4. Sensitivity for detection of metastatic bone disease in all subjects was 78% for CT/MRI, 82% for bone scintigraphy, 71% for [123/131I]-MIBG, 90% for [18F]-FDA PET), and 76% for [18F]-FDG PET. The difference in sensitivity was borderline significant between [18F]-FDA PET and [123/131I]-MIBG (P=0.052).

Table 4

Sensitivity in detection of bone metastatic involvement in subjects with malignant pheochromocytoma and paraganglioma

Malignant pheochromocytoma with bone metastases
MethodAll subjectsSDHB positiveSDHB negativeP (SDHB positive versus SDHB negative)
CT/MRI (%, positive/all)78 (38/49)96 (22/23)65 (17/26)0.01
Bone scintigraphy82 (32/39)95 (18/19)70 (14/20)0.09
[123/131I]-MIBG71 (34/48)65 (15/23)76 (19/25)NS
[18F]-FDA90 (36/40)79 (15/19)100 (21/21)0.04
[18F]-FDG76 (19/25)92 (11/12)62 (8/13)0.16

Comparison of sensitivity between methods in each group (McNemar test): all subjects: [18F]-FDA versus [123/131I]-MIBG: P=0.052. SDHB-positive subjects: CT/MRI versus [123/131I]-MIBG: P=0,046, SDHB-negative subjects: [18F]-FDA versus CT/MRI: P=0.008, [18F]-FDA versus [18F]-FDG: P=0.07, [18F]-FDA versus bone scintigraphy, P=0.04, [18F]-FDA versus [123/131I]-MIBG: P=0.04. CT/MRI, computed tomography or magnetic resonance imaging; [123/131I]-MIBG, [123I] or [131I]-metaiodobenzylguanidine scintigraphy; [18F]-FDA, [18F]-fluorodopamine positron emission tomography; [18F]-FDG, [18F]-fluorodeoxyglucose positron emission tomography; NS, non-significant.

Analysis of subjects with SDHB mutation revealed that the modalities with the highest sensitivity for detecting bone metastases in subjects with SDHB mutation were CT/MRI (96%), bone scintigraphy (95%), and [18F]-FDG PET (92%). Other modalities had lower sensitivities, including [18F]-FDA PET (79%) and [123/131I]-MIBG (65%). The difference in sensitivity for bone metastases between CT/MRI and [123/131I]-MIBG was significant (P=0.046; Table 4). In four subjects with SDHB mutation (patient nos 1, 4, 8, and 16 in Table 2 and Fig. 1), bone scintigraphy and CT/MRI demonstrated bone metastases despite negative results with the specific functional imaging agents ([123/131I]-MIBG and [18F]-FDA PET). In two other patients (nos 24 and 25), bone scintigraphy was likely falsely positive (lesions could not be confirmed by other imaging studies or with repeated bone scintigraphy). In one subject (no. 23), bone metastases (multiple) were confirmed only by [18F]-FDA PET.

Figure 1
Figure 1

Bone involvement in subject with SDHB-positive malignant paraganglioma after left adrenalectomy and nephrectomy (subject no. 16, Table 2).Bone scintigraphy shows a metastatic lesion in the right lesser trochanter (arrow) and probable degenerative disease in the right humeral head (arrowhead). Anterior reprojected images with [18F]-fluorodopamine positron emission tomography ([18F]-FDA PET) and [123I]-metaiodobenzylguanidine scintigraphy ([123I]-MIBG) are without obvious bone involvement.

Citation: Endocrine-Related Cancer 15, 1; 10.1677/ERC-07-0217

In subjects without SDHB mutation, the highest sensitivity for bone metastases was found with [18F]-FDA PET (100%). This was followed by [123/131I]-MIBG (76%), bone scintigraphy (70%), CT/MRI (65%), and [18F]-FDG PET (62%; Table 4). The significant differences were found between [18F]-FDA and CT/MRI (P=0.008), [123/131I]-MIBG (P=0.04), and bone scintigraphy (P=0.04; Table 4). Functional imaging studies with specific agents ([123I]-MIBG and [18F]-FDA PET) were the only methods which identified bone involvement in subject nos 14 and 17, and [18F]-FDA PET alone identified bone metastases in subject nos 5 (Fig. 2) and 6. In subject nos 3 and 18, only bone scintigraphy and [18F]-FDA PET identified bone metastases (Table 3).

Figure 2
Figure 2

Bone involvement in subject with SDHB-negative malignant paraganglioma (subject no. 5, Table 3). Multiple bone lesions (skull, thoracic spine, sacrum, and pelvis) are shown in the anterior reprojected image with [18F]-fluorodopamine positron emission tomography ([18F]-FDA PET) but not in the anterior reprojected [18F]-fluorodeoxyglucose positron emission tomography ([18F]-FDG PET) image, bone scintigraphy, or [123I]-metaiodobenzylguanidine scan ([123I]-MIBG).

Citation: Endocrine-Related Cancer 15, 1; 10.1677/ERC-07-0217

Comparison of sensitivities between subjects with and without SDHB mutation showed significantly better results in subjects with SDHB mutation for CT/MRI (P=0.01). In contrast, in subjects without SDHB mutation, [18F]-FDA PET showed significantly better results in detection of bone metastases (P=0.04; Table 4).

Subgroup analysis of subjects with malignant PGL (primary tumor in extra-adrenal location, 50 subjects) compared with those with malignant PHEO (primary tumor in adrenal location, 21 subjects) showed significant differences in the frequency of biochemical phenotypes expressed between the two groups. Phenotypes typical for less-differentiated tumors (dopamine secretion or failure to secrete catecholamines) were seen in 42% of subjects with malignant PGL versus 14% of subjects with malignant PHEO (P=0.03). Differences were also found in the frequency of liver metastases (57% of subjects with malignant PHEO versus 37% of subjects with malignant PGL, P=0.04). No significant differences were found in the presence of abdominal/pelvic, lung, and bone metastases between these two groups.

In the 37 subjects with malignant PGL and bone metastases, [18F]-FDA PET detected bone lesions with a sensitivity of 87% (27/31), compared with 86% (32/37) for CT/MR, 82% (23/28) for bone scintigraphy, 82% (18/22) for [18F]-FDG PET, and 70% (26/37) for [123/131I]-MIBG. These differences were not statistically significant.

In the 12 subjects with malignant PHEO with bone metastases, [18F]-FDA PET detected bone lesions with a sensitivity of 100% (9/9), followed by 82% for bone scintigraphy (9/11), 73% for [123/131I]-MIBG (8/11), 58% for CT/MRI (7/12), and 33% for [18F]-FDG PET (1/3). These differences were not statistically significant. However, in subjects with malignant PGL, CT/MRI demonstrated borderline significantly better sensitivity in detection of bone metastases than in subjects with malignant PHEO (86% vs 58%, P=0.051).

Discussion

In the present study, we found a high frequency of metastatic bone disease in subjects with metastatic PHEO/PGL (69%) compared with liver (39%) and lung (32%) involvement. Subjects with malignant PHEO/PGL and SHDB mutations showed a significantly higher frequency of bone involvement of pelvic, sacral, and long bones than subjects without SHDB mutations. The highest sensitivity for detecting bone metastases in all these patients regardless of SDHB mutation status was demonstrated with [18F]-FDA (90%), whereas [123/131I]-MIBG (71%) had the lowest sensitivity. In SDHB-positive patients, [18F]-FDG PET had highest sensitivity (92%) among PET-based techniques, whereas in SDHB-negative patients, [18F]-FDA PET had the highest sensitivity (100%), However, bone scintigraphy, a readily available study that is relatively cheap compared with other functional imaging modalities, had overall sensitivity of 82%. No significant differences were found in sensitivities for the detection of bone metastases when the analysis was performed comparing subjects with tumors of adrenal versus extra-adrenal origins.

The high incidence of bone metastases in our patient population is similar to previously published studies in other patients with metastatic PHEO (James et al. 1972, Lynn et al. 1986, Fitzgerald et al. 2006). Overall, the most frequent sites of bone metastases were spine (thoracic and lumbar), pelvis with sacrum, and long bones (mainly femur), which is also in concordance with the study of Lynn et al. (1986).

Bone scintigraphy with Tc-99m-methylene diphosphonate is a non-specific imaging method for detecting metastatic bone disease. Tc-99m-methylene diphosphonate is taken up by sites of active bone formation, not only in areas of bone metastases but also in areas associated with degenerative disease, trauma, and inflammation (Krasnow et al. 1997, Fogelman et al. 2005). Bone scintigraphy can also be falsely negative in tumors with primarily lytic osseous metastases (e.g. multiple myeloma; Roodman 2004). This may also limit diagnostic sensitivity in other tumors with predominantly lytic metastases such as PHEO (James et al. 1972, Krasnow et al. 1997). Bone scintigraphy is also of limited use in monitoring therapeutic response because induced osteoblastic response persists for a considerable time after successful treatment (Fogelman et al. 2005). In our patients with malignant PHEO, bone scintigraphy demonstrated a relatively high sensitivity (82%) for bone metastases in the group as a whole, comparable with the study of Lynn et al. (1986) which found a sensitivity of 74% for bone scintigraphy in lesion detection. Additionally, in our study, bone scintigraphy tended to be more sensitive in subjects with SDHB mutation compared with those without the mutation.

Unlike other cancers, most PHEO cells possess the ability to take up and store catecholamines. This allows specific imaging with MIBG and [18F]-FDA PET (Ilias et al. 2005). On the other hand, less-differentiated cells in malignant PHEO/PGL may be more avid for [18F]-FDG, a non-specific agent which is taken up by the cell glucose transporter and correlates with high metabolic rate of glucose (Pacak et al. 2004, Mamede et al. 2006). In the present study, we found that subjects with SDHB mutation, whose tumors were most likely less differentiated (more than one half of subjects with SDHB mutation presented with elevated dopamine or even failed to secrete catecholamines) than those without SDHB mutation, imaging with less specific agents such as Tc-99m-methylene diphosphonate and [18F]-FDG was superior to more specific agents such as [18F]-FDA in detecting bone metastases. Only in one SDHB-positive patient (no. 23) was [18F]-FDA positive and [18F]-FDG PET and [123I]-MIBG scintigraphy negative for bone metastases. In contrast, in patients without SDHB mutation whose tumors are, in general, relatively well-differentiated, the specific agent [18F]-FDA showed excellent sensitivity in detecting bone metastases and was the only imaging modality which detected bone metastases in two subjects.

Although it is a specific imaging agent, [123/131I]-MIBG scintigraphy showed limited sensitivity for detecting bone metastases in metastatic PHEO/PGL (71%), with no differences found between SDHB-positive and -negative subject groups. Twenty years ago, Lynn et al. (1986) showed a limited sensitivity of 55% with [131I]-MIBG scintigraphy for the detection of bone metastatic lesions, which was also below that of CT and bone scintigraphy. These results along with others demonstrate the limitations of using [123/131I]-MIBG scintigraphy for therapeutic decision making in subjects with metastatic PHEO (Shulkin et al. 1999, van der Harst et al. 2001, Ilias et al. 2003, Mamede et al. 2006).

Although CT and MRI have excellent sensitivity for detecting most PHEO, these anatomical imaging approaches lack the specificity required to unequivocally identify a mass as a PHEO/PGL. The higher specificity of functional imaging – with the test of choice at most institutions currently being [123I]-MIBG scintigraphy – offers an approach to overcome the limitations of anatomical imaging (Pacak et al. 2007). Thus, although CT and MRI had the highest sensitivity in detecting bone metastatic lesions in SDHB-positive patients, we still recommend performing functional imaging studies.

Our study has a number of limitations. Due to its retrospective design, we cannot exclude potential observer bias. Other limitations are that not all subjects were contemporaneously investigated with every modality. In particular, only 25 patients with malignant PHEO/PGL underwent contemporaneous [18F]-FDG PET imaging. Another limitation is that [131I]-MIBG, which is inferior to [123I]-MIBG (Furuta et al. 1999), was used in seven patients. We also did not have a histolopathologic gold standard for determining the presence or absence of bone metastases, as bone biopsies were not performed. Despite the availability of many good α- and β-adrenoceptor blockers and other drugs, surgical manipulation of a tumor can be dangerous since full adrenoceptor blockade is impossible. Thus, biopsy of PHEO is less common than for other tumors and very often unnecessary when biochemical and specific imaging studies as well as a patient's history suggest the diagnosis. Only those bone abnormalities that were highly suspicious of metastatic disease were included in the present study.

In summary, we found a high frequency of metastatic bone involvement among subjects with malignant PHEO. Screening for bone metastases should be performed in all subjects being evaluated for this disease. Malignant PHEO subjects with and without SDHB mutation had similar rates of bone involvement, but those with the mutation demonstrated higher incidences of pelvic (with sacrum) and long bone disease compared with those without it.

In subjects with SDHB mutation, the functional imaging which best visualized bone metastases were the non-specific modalities – bone scanning and [18F]-FDG PET, whereas in subjects without SDHB mutation, a highly specific imaging study – [18F]-FDA PET was the most sensitive. Thus, from a functional imaging standpoint, bone scintigraphy should be used in the staging of subjects with malignant PHEO, particularly in patients with SDHB mutation. [18F]-FDG PET is also highly recommended in SDHB mutation patients, whereas [18F]-FDA PET is recommended in patients without the mutation.

Acknowledgements

This research was supported by the Intramural Research Program of the NICHD/NIH and in part by the Research project of Czech Ministry of Education 0021620808. The authors have no conflict of interest to disclose.

References

  • Amar L, Bertherat J, Baudin E, Ajzenberg C, Bressac-de Paillerets B, Chabre O, Chamontin B, Delemer B, Giraud S & Murat A et al. 2005 Genetic testing in pheochromocytoma or functional paraganglioma. Journal of Clinical Oncology 23 88128818.

    • Search Google Scholar
    • Export Citation
  • Averbuch SD, Steakley CS, Young RC, Gelmann EP, Goldstein DS, Stull R & Keiser HR 1988 Malignant pheochromocytoma: effective treatment with a combination of cyclophosphamide, vincristine, and dacarbazine. Annals of Internal Medicine 109 267273.

    • Search Google Scholar
    • Export Citation
  • Benn DE, Gimenez-Roqueplo AP, Reilly JR, Bertherat J, Burgess J, Byth K, Croxson M, Dahia PL, Elston M & Gimm O et al. 2006 Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. Journal of Clinical Endocrinology and Metabolism 91 827836.

    • Search Google Scholar
    • Export Citation
  • Brouwers FM, Eisenhofer G, Tao JJ, Kant JA, Adams KT, Linehan WM & Pacak K 2006 High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing. Journal of Clinical Endocrinology and Metabolism 91 45054509.

    • Search Google Scholar
    • Export Citation
  • Eisenhofer G, Goldstein DS, Stull R, Keiser HR, Sunderland T, Murphy DL & Kopin IJ 1986 Simultaneous liquid-chromatographic determination of 3,4-dihydroxyphenylglycol, catecholamines, and 3,4-dihydroxyphenylalanine in plasma, and their responses to inhibition of monoamine oxidase. Clinical Chemistry 32 20302033.

    • Search Google Scholar
    • Export Citation
  • Eriksson B, Bergstrom M, Orlefors H, Sundin A, Oberg K & Langstrom B 2000 Use of PET in neuroendocrine tumors. In vivo applications and in vitro studies. Quarterly Journal of Nuclear Medicine 44 6876.

    • Search Google Scholar
    • Export Citation
  • Fitzgerald PA, Goldsby RE, Huberty JP, Price DC, Hawkins RA, Veatch JJ, Dela Cruz F, Jahan TM, Linker CA & Damon L et al. 2006 Malignant pheochromocytomas and paragangliomas: a phase II study of therapy with high-dose 131I-metaiodobenzylguanidine (131I-MIBG). Annals of the New York Academy of Sciences 1073 465490.

    • Search Google Scholar
    • Export Citation
  • Fogelman I, Cook G, Israel O & Van der Wall H 2005 Positron emission tomography and bone metastases. Seminars in Nuclear Medicine 35 135142.

  • Franzius C, Hermann K, Weckesser M, Kopka K, Juergens KU, Vormoor J & Schober O 2006 Whole-body PET/CT with 11C-meta-hydroxyephedrine in tumors of the sympathetic nervous system: feasibility study and comparison with 123I-MIBG SPECT/CT. Journal of Nuclear Medicine 47 16351642.

    • Search Google Scholar
    • Export Citation
  • Furuta N, Kiyota H, Yoshigoe F, Hasegawa N & Ohishi Y 1999 Diagnosis of pheochromocytoma using [123I]-compared with [131I]-metaiodobenzylguanidine scintigraphy. International Journal of Urology 6 119124.

    • Search Google Scholar
    • Export Citation
  • Goldstein RE, O'Neill JA Jr, Holcomb GW III, Morgan WM III, Neblett WW III, Oates JA, Brown N, Nadeau J, Smith B & Page DL et al. 1999 Clinical experience over 48 years with pheochromocytoma. Annals of Surgery 229 755764 (discussion 764-756)

    • Search Google Scholar
    • Export Citation
  • Hamaoka T, Madewell JE, Podoloff DA, Hortobagyi GN & Ueno NT 2004 Bone imaging in metastatic breast cancer. Journal of Clinical Oncology 22 29422953.

  • van der Harst E, de Herder WW, Bruining HA, Bonjer HJ, de Krijger RR, Lamberts SW, van de Meiracker AH, Boomsma F, Stijnen T & Krenning EP et al. 2001 [(123)I]metaiodobenzylguanidine and [(111)In]octreotide uptake in begnign and malignant pheochromocytomas. Journal of Clinical Endocrinology and Metabolism 86 685693.

    • Search Google Scholar
    • Export Citation
  • Hoegerle S, Nitzsche E, Altehoefer C, Ghanem N, Manz T, Brink I, Reincke M, Moser E & Neumann HP 2002 Pheochromocytomas: detection with 18F DOPA whole body PET – initial results. Radiology 222 507512.

    • Search Google Scholar
    • Export Citation
  • Ilias I, Yu J, Carrasquillo JA, Chen CC, Eisenhofer G, Whatley M, McElroy B & Pacak K 2003 Superiority of 6-[18F]-fluorodopamine positron emission tomography versus [131I]-metaiodobenzylguanidine scintigraphy in the localization of metastatic pheochromocytoma. Journal of Clinical Endocrinology and Metabolism 88 40834087.

    • Search Google Scholar
    • Export Citation
  • Ilias I, Shulkin B & Pacak K 2005 New functional imaging modalities for chromaffin tumors, neuroblastomas and ganglioneuromas. Trends in Endocrinology and Metabolism 16 6672.

    • Search Google Scholar
    • Export Citation
  • James RE, Baker HL Jr & Scanlon PW 1972 The roentgenologic aspects of metastatic pheochromocytoma. American Journal of Roentgenology, Radium Therapy, and Nuclear Medicine 115 783793.

    • Search Google Scholar
    • Export Citation
  • John H, Ziegler WH, Hauri D & Jaeger P 1999 Pheochromocytomas: can malignant potential be predicted? Urology 53 679683.

  • Kimura N, Watanabe T, Noshiro T, Shizawa S & Miura Y 2005 Histological grading of adrenal and extra-adrenal pheochromocytomas and relationship to prognosis: a clinicopathological analysis of 116 adrenal pheochromocytomas and 30 extra-adrenal sympathetic paragangliomas including 38 malignant tumors. Endocrine Pathology 16 2332.

    • Search Google Scholar
    • Export Citation
  • Krasnow AZ, Hellman RS, Timins ME, Collier BD, Anderson T & Isitman AT 1997 Diagnostic bone scanning in oncology. Seminars in Nuclear Medicine 27 107141.

  • Lehnert H, Mundschenk J & Hahn K 2004 Malignant pheochromocytoma. Frontiers of Hormone Research 31 155162.

  • Lenders JW, Eisenhofer G, Armando I, Keiser HR, Goldstein DS & Kopin IJ 1993 Determination of metanephrines in plasma by liquid chromatography with electrochemical detection. Clinical Chemistry 39 97103.

    • Search Google Scholar
    • Export Citation
  • Lenders JW, Eisenhofer G, Mannelli M & Pacak K 2005 Phaeochromocytoma. Lancet 366 665675.

  • Loh KC, Fitzgerald PA, Matthay KK, Yeo PP & Price DC 1997 The treatment of malignant pheochromocytoma with iodine-131 metaiodobenzylguanidine (131I-MIBG): a comprehensive review of 116 reported patients. Journal of Endocrinological Investigation 20 648658.

    • Search Google Scholar
    • Export Citation
  • Lynn MD, Braunstein EM, Wahl RL, Shapiro B, Gross MD & Rabbani R 1986 Bone metastases in pheochromocytoma: comparative studies of efficacy of imaging. Radiology 160 701706.

    • Search Google Scholar
    • Export Citation
  • Mamede M, Carrasquillo JA, Chen CC, Del Corral P, Whatley M, Ilias I, Ayala A & Pacak K 2006 Discordant localization of 2-[18F]-fluoro-2-deoxy-d-glucose in 6-[18F]-fluorodopamine- and [(123)I]-metaiodobenzylguanidine-negative metastatic pheochromocytoma sites. Nuclear Medicine Communications 27 3136.

    • Search Google Scholar
    • Export Citation
  • Mann GN, Link JM, Pham P, Pickett CA, Byrd DR, Kinahan PE, Krohn KA & Mankoff DA 2006 [11C]Metahydroxyephedrine and [18F]fluorodeoxyglucose positron emission tomography improve clinical decision making in suspected pheochromocytoma. Annals of Surgical Oncology 13 187197.

    • Search Google Scholar
    • Export Citation
  • O'Riordain DS, Young WF Jr, Grant CS, Carney JA & van Heerden JA 1996 Clinical spectrum and outcome of functional extraadrenal paraganglioma. World Journal of Surgery 20 916921.

    • Search Google Scholar
    • Export Citation
  • Pacak K, Eisenhofer G & Goldstein DS 2004 Functional imaging of endocrine tumors: role of positron emission tomography. Endocrine Reviews 25 568580.

    • Search Google Scholar
    • Export Citation
  • Pacak K, Eisenhofer G, Ahlman H, Bornstein SR, Gimenez-Roqueplo AP, Grossman AB, Kimura N, Mannelli M, McNicol AM & Tischler AS 2007 Pheochromocytoma: recommendations for clinical practice from the First International Symposium. October 2005. Nature Clinical Practice. Endocrinology and Metabolism 3 92102.

    • Search Google Scholar
    • Export Citation
  • Plouin PF, Chatellier G, Fofol I & Corvol P 1997 Tumor recurrence and hypertension persistence after successful pheochromocytoma operation. Hypertension 29 11331139.

    • Search Google Scholar
    • Export Citation
  • Roodman GD 2004 Mechanisms of bone metastasis. New England Journal of Medicine 350 16551664.

  • Rufini V, Calcagni ML & Baum RP 2006 Imaging of neuroendocrine tumors. Seminars in Nuclear Medicine 36 228247.

  • Schlumberger M, Gicquel C, Lumbroso J, Tenenbaum F, Comoy E, Bosq J, Fonseca E, Ghillani PP, Aubert B & Travagli JP et al. 1992 Malignant pheochromocytoma: clinical, biological, histologic and therapeutic data in a series of 20 patients with distant metastases. Journal of Endocrinological Investigation 15 631642.

    • Search Google Scholar
    • Export Citation
  • Shulkin BL, Thompson NW, Shapiro B, Francis IR & Sisson JC 1999 Pheochromocytomas: imaging with 2-[fluorine-18]fluoro-2-deoxy-d-glucose PET. Radiology 212 3541.

    • Search Google Scholar
    • Export Citation
  • Sundin A, Garske U & Orlefors H 2007 Nuclear imaging of neuroendocrine tumours. Best Practice and Research. Clinical Endocrinology and Metabolism 21 6985.

    • Search Google Scholar
    • Export Citation
  • Timmers HJ, Kozupa A, Eisenhofer G, Raygada M, Adams KT, Solis D, Lenders JW & Pacak K 2007 Clinical presentations, biochemical phenotypes, and genotype–phenotype correlations in patients with succinate dehydrogenase subunit B-associated pheochromocytomas and paragangliomas. Journal of Clinical Endocrinology and Metabolism 92 779786.

    • Search Google Scholar
    • Export Citation
  • Trampal C, Engler H, Juhlin C, Bergstrom M & Langstrom B 2004 Pheochromocytomas: detection with 11C hydroxyephedrine PET. Radiology 230 423428.

  • Vassilopoulou-Sellin R 1998 Clinical outcome of 50 patients with malignant abdominal paragangliomas and malignant pheochromocytomas. Endocrine-Related Cancer 5 5968.

    • Search Google Scholar
    • Export Citation
  • Yu J & Pacak K 2002 Management of malignant pheochromocytoma. Endocrinologist 12 291299.

  • Zarnegar R, Kebebew E, Duh QY & Clark OH 2006 Malignant pheochromocytoma. Surgical Oncology Clinics of North America 15 555571.

 

Society for Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 1128 84 22
PDF Downloads 452 46 3
  • View in gallery

    Bone involvement in subject with SDHB-positive malignant paraganglioma after left adrenalectomy and nephrectomy (subject no. 16, Table 2).Bone scintigraphy shows a metastatic lesion in the right lesser trochanter (arrow) and probable degenerative disease in the right humeral head (arrowhead). Anterior reprojected images with [18F]-fluorodopamine positron emission tomography ([18F]-FDA PET) and [123I]-metaiodobenzylguanidine scintigraphy ([123I]-MIBG) are without obvious bone involvement.

  • View in gallery

    Bone involvement in subject with SDHB-negative malignant paraganglioma (subject no. 5, Table 3). Multiple bone lesions (skull, thoracic spine, sacrum, and pelvis) are shown in the anterior reprojected image with [18F]-fluorodopamine positron emission tomography ([18F]-FDA PET) but not in the anterior reprojected [18F]-fluorodeoxyglucose positron emission tomography ([18F]-FDG PET) image, bone scintigraphy, or [123I]-metaiodobenzylguanidine scan ([123I]-MIBG).

  • Amar L, Bertherat J, Baudin E, Ajzenberg C, Bressac-de Paillerets B, Chabre O, Chamontin B, Delemer B, Giraud S & Murat A et al. 2005 Genetic testing in pheochromocytoma or functional paraganglioma. Journal of Clinical Oncology 23 88128818.

    • Search Google Scholar
    • Export Citation
  • Averbuch SD, Steakley CS, Young RC, Gelmann EP, Goldstein DS, Stull R & Keiser HR 1988 Malignant pheochromocytoma: effective treatment with a combination of cyclophosphamide, vincristine, and dacarbazine. Annals of Internal Medicine 109 267273.

    • Search Google Scholar
    • Export Citation
  • Benn DE, Gimenez-Roqueplo AP, Reilly JR, Bertherat J, Burgess J, Byth K, Croxson M, Dahia PL, Elston M & Gimm O et al. 2006 Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. Journal of Clinical Endocrinology and Metabolism 91 827836.

    • Search Google Scholar
    • Export Citation
  • Brouwers FM, Eisenhofer G, Tao JJ, Kant JA, Adams KT, Linehan WM & Pacak K 2006 High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing. Journal of Clinical Endocrinology and Metabolism 91 45054509.

    • Search Google Scholar
    • Export Citation
  • Eisenhofer G, Goldstein DS, Stull R, Keiser HR, Sunderland T, Murphy DL & Kopin IJ 1986 Simultaneous liquid-chromatographic determination of 3,4-dihydroxyphenylglycol, catecholamines, and 3,4-dihydroxyphenylalanine in plasma, and their responses to inhibition of monoamine oxidase. Clinical Chemistry 32 20302033.

    • Search Google Scholar
    • Export Citation
  • Eriksson B, Bergstrom M, Orlefors H, Sundin A, Oberg K & Langstrom B 2000 Use of PET in neuroendocrine tumors. In vivo applications and in vitro studies. Quarterly Journal of Nuclear Medicine 44 6876.

    • Search Google Scholar
    • Export Citation
  • Fitzgerald PA, Goldsby RE, Huberty JP, Price DC, Hawkins RA, Veatch JJ, Dela Cruz F, Jahan TM, Linker CA & Damon L et al. 2006 Malignant pheochromocytomas and paragangliomas: a phase II study of therapy with high-dose 131I-metaiodobenzylguanidine (131I-MIBG). Annals of the New York Academy of Sciences 1073 465490.

    • Search Google Scholar
    • Export Citation
  • Fogelman I, Cook G, Israel O & Van der Wall H 2005 Positron emission tomography and bone metastases. Seminars in Nuclear Medicine 35 135142.

  • Franzius C, Hermann K, Weckesser M, Kopka K, Juergens KU, Vormoor J & Schober O 2006 Whole-body PET/CT with 11C-meta-hydroxyephedrine in tumors of the sympathetic nervous system: feasibility study and comparison with 123I-MIBG SPECT/CT. Journal of Nuclear Medicine 47 16351642.

    • Search Google Scholar
    • Export Citation
  • Furuta N, Kiyota H, Yoshigoe F, Hasegawa N & Ohishi Y 1999 Diagnosis of pheochromocytoma using [123I]-compared with [131I]-metaiodobenzylguanidine scintigraphy. International Journal of Urology 6 119124.

    • Search Google Scholar
    • Export Citation
  • Goldstein RE, O'Neill JA Jr, Holcomb GW III, Morgan WM III, Neblett WW III, Oates JA, Brown N, Nadeau J, Smith B & Page DL et al. 1999 Clinical experience over 48 years with pheochromocytoma. Annals of Surgery 229 755764 (discussion 764-756)

    • Search Google Scholar
    • Export Citation
  • Hamaoka T, Madewell JE, Podoloff DA, Hortobagyi GN & Ueno NT 2004 Bone imaging in metastatic breast cancer. Journal of Clinical Oncology 22 29422953.

  • van der Harst E, de Herder WW, Bruining HA, Bonjer HJ, de Krijger RR, Lamberts SW, van de Meiracker AH, Boomsma F, Stijnen T & Krenning EP et al. 2001 [(123)I]metaiodobenzylguanidine and [(111)In]octreotide uptake in begnign and malignant pheochromocytomas. Journal of Clinical Endocrinology and Metabolism 86 685693.

    • Search Google Scholar
    • Export Citation
  • Hoegerle S, Nitzsche E, Altehoefer C, Ghanem N, Manz T, Brink I, Reincke M, Moser E & Neumann HP 2002 Pheochromocytomas: detection with 18F DOPA whole body PET – initial results. Radiology 222 507512.

    • Search Google Scholar
    • Export Citation
  • Ilias I, Yu J, Carrasquillo JA, Chen CC, Eisenhofer G, Whatley M, McElroy B & Pacak K 2003 Superiority of 6-[18F]-fluorodopamine positron emission tomography versus [131I]-metaiodobenzylguanidine scintigraphy in the localization of metastatic pheochromocytoma. Journal of Clinical Endocrinology and Metabolism 88 40834087.

    • Search Google Scholar
    • Export Citation
  • Ilias I, Shulkin B & Pacak K 2005 New functional imaging modalities for chromaffin tumors, neuroblastomas and ganglioneuromas. Trends in Endocrinology and Metabolism 16 6672.

    • Search Google Scholar
    • Export Citation
  • James RE, Baker HL Jr & Scanlon PW 1972 The roentgenologic aspects of metastatic pheochromocytoma. American Journal of Roentgenology, Radium Therapy, and Nuclear Medicine 115 783793.

    • Search Google Scholar
    • Export Citation
  • John H, Ziegler WH, Hauri D & Jaeger P 1999 Pheochromocytomas: can malignant potential be predicted? Urology 53 679683.

  • Kimura N, Watanabe T, Noshiro T, Shizawa S & Miura Y 2005 Histological grading of adrenal and extra-adrenal pheochromocytomas and relationship to prognosis: a clinicopathological analysis of 116 adrenal pheochromocytomas and 30 extra-adrenal sympathetic paragangliomas including 38 malignant tumors. Endocrine Pathology 16 2332.

    • Search Google Scholar
    • Export Citation
  • Krasnow AZ, Hellman RS, Timins ME, Collier BD, Anderson T & Isitman AT 1997 Diagnostic bone scanning in oncology. Seminars in Nuclear Medicine 27 107141.

  • Lehnert H, Mundschenk J & Hahn K 2004 Malignant pheochromocytoma. Frontiers of Hormone Research 31 155162.

  • Lenders JW, Eisenhofer G, Armando I, Keiser HR, Goldstein DS & Kopin IJ 1993 Determination of metanephrines in plasma by liquid chromatography with electrochemical detection. Clinical Chemistry 39 97103.

    • Search Google Scholar
    • Export Citation
  • Lenders JW, Eisenhofer G, Mannelli M & Pacak K 2005 Phaeochromocytoma. Lancet 366 665675.

  • Loh KC, Fitzgerald PA, Matthay KK, Yeo PP & Price DC 1997 The treatment of malignant pheochromocytoma with iodine-131 metaiodobenzylguanidine (131I-MIBG): a comprehensive review of 116 reported patients. Journal of Endocrinological Investigation 20 648658.

    • Search Google Scholar
    • Export Citation
  • Lynn MD, Braunstein EM, Wahl RL, Shapiro B, Gross MD & Rabbani R 1986 Bone metastases in pheochromocytoma: comparative studies of efficacy of imaging. Radiology 160 701706.

    • Search Google Scholar
    • Export Citation
  • Mamede M, Carrasquillo JA, Chen CC, Del Corral P, Whatley M, Ilias I, Ayala A & Pacak K 2006 Discordant localization of 2-[18F]-fluoro-2-deoxy-d-glucose in 6-[18F]-fluorodopamine- and [(123)I]-metaiodobenzylguanidine-negative metastatic pheochromocytoma sites. Nuclear Medicine Communications 27 3136.

    • Search Google Scholar
    • Export Citation
  • Mann GN, Link JM, Pham P, Pickett CA, Byrd DR, Kinahan PE, Krohn KA & Mankoff DA 2006 [11C]Metahydroxyephedrine and [18F]fluorodeoxyglucose positron emission tomography improve clinical decision making in suspected pheochromocytoma. Annals of Surgical Oncology 13 187197.

    • Search Google Scholar
    • Export Citation
  • O'Riordain DS, Young WF Jr, Grant CS, Carney JA & van Heerden JA 1996 Clinical spectrum and outcome of functional extraadrenal paraganglioma. World Journal of Surgery 20 916921.

    • Search Google Scholar
    • Export Citation
  • Pacak K, Eisenhofer G & Goldstein DS 2004 Functional imaging of endocrine tumors: role of positron emission tomography. Endocrine Reviews 25 568580.

    • Search Google Scholar
    • Export Citation
  • Pacak K, Eisenhofer G, Ahlman H, Bornstein SR, Gimenez-Roqueplo AP, Grossman AB, Kimura N, Mannelli M, McNicol AM & Tischler AS 2007 Pheochromocytoma: recommendations for clinical practice from the First International Symposium. October 2005. Nature Clinical Practice. Endocrinology and Metabolism 3 92102.

    • Search Google Scholar
    • Export Citation
  • Plouin PF, Chatellier G, Fofol I & Corvol P 1997 Tumor recurrence and hypertension persistence after successful pheochromocytoma operation. Hypertension 29 11331139.

    • Search Google Scholar
    • Export Citation
  • Roodman GD 2004 Mechanisms of bone metastasis. New England Journal of Medicine 350 16551664.

  • Rufini V, Calcagni ML & Baum RP 2006 Imaging of neuroendocrine tumors. Seminars in Nuclear Medicine 36 228247.

  • Schlumberger M, Gicquel C, Lumbroso J, Tenenbaum F, Comoy E, Bosq J, Fonseca E, Ghillani PP, Aubert B & Travagli JP et al. 1992 Malignant pheochromocytoma: clinical, biological, histologic and therapeutic data in a series of 20 patients with distant metastases. Journal of Endocrinological Investigation 15 631642.

    • Search Google Scholar
    • Export Citation
  • Shulkin BL, Thompson NW, Shapiro B, Francis IR & Sisson JC 1999 Pheochromocytomas: imaging with 2-[fluorine-18]fluoro-2-deoxy-d-glucose PET. Radiology 212 3541.

    • Search Google Scholar
    • Export Citation
  • Sundin A, Garske U & Orlefors H 2007 Nuclear imaging of neuroendocrine tumours. Best Practice and Research. Clinical Endocrinology and Metabolism 21 6985.

    • Search Google Scholar
    • Export Citation
  • Timmers HJ, Kozupa A, Eisenhofer G, Raygada M, Adams KT, Solis D, Lenders JW & Pacak K 2007 Clinical presentations, biochemical phenotypes, and genotype–phenotype correlations in patients with succinate dehydrogenase subunit B-associated pheochromocytomas and paragangliomas. Journal of Clinical Endocrinology and Metabolism 92 779786.

    • Search Google Scholar
    • Export Citation
  • Trampal C, Engler H, Juhlin C, Bergstrom M & Langstrom B 2004 Pheochromocytomas: detection with 11C hydroxyephedrine PET. Radiology 230 423428.

  • Vassilopoulou-Sellin R 1998 Clinical outcome of 50 patients with malignant abdominal paragangliomas and malignant pheochromocytomas. Endocrine-Related Cancer 5 5968.

    • Search Google Scholar
    • Export Citation
  • Yu J & Pacak K 2002 Management of malignant pheochromocytoma. Endocrinologist 12 291299.

  • Zarnegar R, Kebebew E, Duh QY & Clark OH 2006 Malignant pheochromocytoma. Surgical Oncology Clinics of North America 15 555571.