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.
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. | Sex | Age at malignancy (years) | Primary tumor | Sites of metastases | Symptoms related to bone (before diagnosis) | Biochemistry | CT/MRI | BS | [123/131I]-MIBG | [18F]-FDA | [18F]-FDG |
| Patients with bone involvement | |||||||||||
| 1a | F | 38 | EA | a/p, b, li | 0 | NE+DA | 1 | 1 | 0 | 0 | |
| 2 | M | 19 | EA | a/p, b, li, lu, ne | 0 | NE+DA | 1 | 1 | 1 | 1 | 1 |
| 3 | M | 20 | EA | B | Abdominal pain | NE | 1 | 1 | 0 | 1 | |
| 4 | M | 14 | EA | a/p, b, lu | 0 | NE | 1 | 1 | 0 | 0 | |
| 5 | F | 23 | EA | a/p, b | Skull lesion immediately after diagnosis | NE | 1 | 1 | 1 | 1 | 1 |
| 6a | M | 28 | EA (pelvic) + rib mass | a/p, b, lu, ne | Rib fracture diagnosis | NE+E+DA | 1 | 1 | 1 | 1 | 1 |
| 7a | M | 8 | EA (parailiac) | a/p, b | 0 | NE+DA | 1 | 1 | 1 | 1 | |
| 8 | M | 43 | EA | a/p, b, lu, me | 0 | NE+DA | 1 | 1 | 0 | ||
| 9a | M | 39 | EA | a/p, b, me | Back pain, L laminectomy | 0 | 1 | 1 | 0 | 1 | 1 |
| 10 | F | 43 | EA | a/p, b, li | 0 | NE | 1 | 1 | 1 | 1 | |
| 11a | M | 35 | EA (aortic bifurcation) | a/p, b, me | 0 | NE+DA | 1 | 0 | 1 | 1 | |
| 12 | M | 31 | EA | b | 0 | 0 | 1 | 1 | 1 | 1 | |
| 13 | M | 60 | EA (aortic bifurcation) | a/p, b, lu | Pelvic pain | 0 | 1 | 1 | 1 | 1 | 1 |
| 14a | M | 23 | EA (aortic bifurcation) | a/p, b | 0 | NE+DA | 1 | 1 | 1 | 1 | |
| 15a | F | 24 | EA | b | Abdominal pain | NE | 1 | 1 | 1 | 1 | 1 |
| 16 | M | 50 | EA, neck PGL | a/p, b, me | Abdominal pain | DA | 1 | 1 | 0 | 0 | |
| 17 | M | 48 | EA | b | Hip pain | NE | 1 | 1 | 1 | 1 | 1 |
| 18 | F | 36 | EA | a/p, b, li, lu | T2 laminectomy | 0 | 1 | 1 | 1 | 1 | |
| 19 | M | 56 | EA | a/p, b | 0 | NE | 1 | 1 | 1 | 1 | |
| 20 | F | 72 | EA (aortic bifurcation) | a/p, b | 0 | NE+E+DA | 1 | 1 | |||
| 21 | M | 12 | EA | a/p, b, lu | Back pain | NE | 1 | 1 | 1 | 1 | |
| 22 | M | 35 | EA | a/p, b, li | Back pain, T4-T7 laminectomy | NE+DA | 1 | 0 | 0 | 1 | |
| 23 | F | 52 | EA | b.li, lu | 0 | NE | 0 | 0 | 1 | 0 | |
| Patients without bone involvement | |||||||||||
| 24 | F | 55 | RA | a/p, me, ne | NE | 0 | Ribs (repeated examination normal) | 0 | 0 | 0 | |
| 25 | M | 27 | EA, neck PGL | a/p, lu, me | NE+DA | 0 | One lesion in tibia, post-therapeutic scan negative | 0 | 0 | ||
| 26 | F | 38 | EA (pelvic) | a/p, li | NE+DA | 0 | 0 | 0 | 0 | 0 | |
| 27 | F | 53 | EA | a/p, li, lu, ne | NE+DA | 0 | 0 | 0 | 0 | 0 | |
| 28a | F | 45 | EA, neck PGL | a/p | NE | 0 | 0 | 0 | |||
| 29 | F | 36 | EA (urinary bladder) | a/p, me | NE+DA | 0 | 0 | 0 | 0 | ||
| 30 | F | 36 | EA (pelvic) | a/p, lu | NE | 0 | 0 | 0 | |||
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.
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. | Sex | Age at malignancy (years) | Primary tumor | Sites of metastases | Symptoms related to the bone (before diagnosis) | Biochemistry | Comments | CT/MRI | BS | [123/131I]-MIBG | [18F]-FDA | [18F]-FDG |
| Patients with bone involvement | ||||||||||||
| 1 | F | 20 | EA (presacral) | a/p, b, li | Pain from primary lesion | NE+DA | 1 | 0 | 1 | 1 | ||
| 2 | F | 38 | RA, LA | li, b | 0 | NE+E | MEN 2A (sister no. 28) | 1 | 1 | 1 | 1 | |
| 3 | F | 45 | RA | a/p, b, lu | 0 | NE | 0 | 1 | 0 | 1 | ||
| 4 | M | 56 | EA | b | Pain in ribs and shoulder blade, Th5 laminectomy | NE | 1 | 1 | 1 | 1 | ||
| 5 | F | 55 | EA | b | 0 | NE+E | 0 | 0 | 0 | 1 | 0 | |
| 6a | F | 36 | EA | a/p, b, me | 0 | NE | Carcinoid, polycythemia vera | 0 | 0 | 0 | 1 | 0 |
| 7 | F | 44 | LA | a/p, b, li, | 0 | NE | 0 | 0 | 1 | 1 | 0 | |
| 8 | M | 23 | RA, neck PGL | a/p, b.li, me | 0 | NE | SDHD | 0 | 1 | 1 | 1 | 1 |
| 9a | F | 64 | EA (pelvic) | a/p, b | Polymyalgia rheumatica for 7 years before diagnosis | NE | 1 | 1 | 1 | 1 | 1 | |
| 10a | M | 36 | EA, neck PGL | a/p, b, lu | First presentation: meta in the left orbit | NE | 1 | 1 | 1 | |||
| 11 | M | 37 | RA | a/p, b, lu | 0 | NE+E | 1 | 1 | 1 | 1 | ||
| 12 | M | 63 | LA | a/p, b, li, lu | 0 | NE | 0 | 1 | 1 | 1 | 0 | |
| 13 | M | 23 | EA | a/p, b | Chest pain | NE | 1 | 1 | 1 | 1 | 1 | |
| 14a | M | 21 | EA (liver) | b, li, lu | L1 laminectomy before evaluation | NE | 0 | 0 | 1 | 1 | 0 | |
| 15 | F | 42 | LA | a/p, b, li, lu, me | 0 | NE | Pos. family history | 1 | 1 | 0 | 1 | 1 |
| 16 | F | 28 | RA | a/p, b, li, lu | 0 | NE+E | 1 | 1 | 1 | |||
| 17a | F | 54 | RA | a/p, b, li | 0 | NE+E | 0 | 0 | 1 | 1 | ||
| 18a | F | 48 | LA | b, li | 0 | NE | 0 | 1 | 0 | 1 | ||
| 19a | F | 36 | RA | a/p, b | 0 | NE+E | 1 | 1 | 1 | |||
| 20a | F | 55 | RA | b, li | Hypercalcemia | NE | 1 | 1 | 1 | |||
| 21a | F | 59 | EA | a/p, b, lu | 0 | NE+E | 1 | 1 | 1 | 1 | ||
| 22 | F | 67 | EA | b, li, lu | 0 | NE+DA | 1 | 1 | 1 | 1 | ||
| 23 | M | 32 | EA | b | 0 | NE | 1 | 0 | 1 | 1 | ||
| 24 | M | 29 | vs. EA | a/p, b, li. | 0 | NE+E | 1 | 1 | 1 | |||
| 25 | M | 44 | EA | a/p, b, li | Back pain | NE | 1 | 1 | 1 | |||
| 26 | M | 53 | RA | a/p, b, li | 0 | NE+DA | 1 | 1 | ||||
| Patients without bone involvement | ||||||||||||
| 27 | F | 32 | LA | a/p | NE+E | VHL | 0 | 0 | 0 | 0 | 0 | |
| 28 | F | 39 | RA,LA | a/p | NE | MEN 2A (sister no. 2) | 0 | 0 | 0 | 0 | 0 | |
| 29 | F | 15 | Adrenal+kidney | a/p | NE | 0 | 0 | 0 | 0 | 0 | ||
| 30 | F | 48 | EA | a/p | NE | 0 | 0 | 0 | 0 | 0 | ||
| 31 | M | 30 | RA, LA | a/p | NE | VHL | 0 | 0 | 0 | 0 | ||
| 32 | M | 64 | LA | a/p | NE+E | VHL | 0 | 0 | 0 | 0 | ||
| 33 | M | 84 | LA | a/p, li, lu | NE | 0 | 0 | 0 | ||||
| 34 | M | 32 | RA, LA, EA | a/p | NE | 0 | 0 | 0 | ||||
| 35 | M | 72 | RA | a/p, li | NE+E+DA | 0 | 0 | 0 | ||||
| 36a | M | 22 | EA (bladder) | a/p | NE+E | 0 | 0 | 0 | ||||
| 37 | M | 41 | EA | a/p | NE | 0 | 0 | |||||
| 38a | M | 38 | RA | a/p | NE | MEN 2A | 0 | 0 | ||||
| 39a | F | 28 | RA | li, lu | NE+DA | 0 | 0 | |||||
| 40 | M | 50 | EA | a/p, li | NE | 0 | 0 | |||||
| 41 | M | 47 | EA (abdomen, bladder) | a/p, li, lu | NE+DA | 0 | ||||||
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).
Baseline characteristics and distribution of metastases in subjects with malignant pheochromocytoma and paraganglioma with regard to genetic testing
| Variable | All subjects n=71 | SDHB positive n=30 | SDHB negative n=41 | P |
|---|---|---|---|---|
| Gender (male/female) | 38/33 | 17/13 | 21/20 | NS |
| Primary tumor (adrenal/extra-adrenal) | 21/50 | 1/29 | 20/21 | <0.001 |
| Age at primary diagnosis (years) | 36±16 | 34±16 | 38±16 | NS |
| Interval to malignancy (years) | 4.4±6.2 | 3.4±5.9 | 5.2±6.2 | NS |
| Interval to bone metastasis (years) | 5.6±7.9 | 5.1±9.6 | 6.0±6.2 | NS |
| 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/pelvic | 80 (57) | 83 (25) | 78 (31) | NS |
| Bone | 69 (49) | 77 (23) | 63 (26) | NS |
| Liver | 39 (28) | 27 (8) | 49 (20) | 0.09 |
| Lung | 32 (23) | 37 (11) | 29 (12) | NS |
| Other (mediastinum and neck) | 20 (14) | 37 (11) | 7 (3) | 0.005 |
| Location of bone involvement (%, positive) | n=49 | n=23 | n=26 | |
| Skull | 37 (18) | 30 (7) | 42 (11) | NS |
| Cervical spine | 39 (19) | 37 (8) | 50 (13) | NS |
| Thoracic spine | 80 (39) | 83 (19) | 77 (20) | NS |
| Lumbar spine | 78 (38) | 78 (18) | 75 (20) | NS |
| Pelvis and sacrum | 78 (38) | 91 (21) | 65 (17) | 0.04 |
| Long bones (femur, humerus, and tibia) | 53 (26) | 78 (18) | 30 (8) | 0.001 |
| Ribs | 61 (30) | 56 (13) | 65 (17) | NS |
| Other (sternum, scapula, clavicula, and hyoid) | 38 (19) | 43 (10) | 35 (9) | NS |
| Symptoms from bone involvement | 39 (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).
Sensitivity in detection of bone metastatic involvement in subjects with malignant pheochromocytoma and paraganglioma
| Malignant pheochromocytoma with bone metastases | ||||
|---|---|---|---|---|
| Method | All subjects | SDHB positive | SDHB negative | P (SDHB positive versus SDHB negative) |
| CT/MRI (%, positive/all) | 78 (38/49) | 96 (22/23) | 65 (17/26) | 0.01 |
| Bone scintigraphy | 82 (32/39) | 95 (18/19) | 70 (14/20) | 0.09 |
| [123/131I]-MIBG | 71 (34/48) | 65 (15/23) | 76 (19/25) | NS |
| [18F]-FDA | 90 (36/40) | 79 (15/19) | 100 (21/21) | 0.04 |
| [18F]-FDG | 76 (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.
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).
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.
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