Abstract
The purpose of this study was to present the characteristics and outcome of patients with proven pheochromocytoma or paraganglioma who had false-negative iodine-123 metaiodobenzylguanidine single photon emission computed tomography (123I-MIBG SPECT). Twenty-one patients with false-negative 123I-MIBG SPECT (7 males, 14 females), aged 13–55 years (mean: 41.40 years), were included. We classified them as nonmetastatic or metastatic according to the stage of the disease at the time of false-negative 123I-MIBG SPECT study, the location and size of the tumor, plasma and urinary catecholamine and metanephrine levels, genetic mutations, and outcome in terms of occurrence and progression of metastases and death. Thirteen patients were evaluated for metastatic tumors, while the remaining eight were seen for nonmetastatic disease. All primary tumors and multiple metastatic foci did not show avid 123I-MIBG uptake regardless of the tumor diameter. The majority of patients had extraadrenal tumors with hypersecretion of normetanephrine or norepinephrine. SDHB mutations were present in 52% (n=11) of cases, RET mutation in 4% (n=1), and the rest were apparently sporadic. Twenty-four percent (n=5) had metastatic disease on initial presentation. Fourteen patients were followed for 3–7 years. Of them, 71% (n=10) had metastatic disease and the majority had SDHB mutations. Nine are still alive, while five (four with SDHB) died due to metastatic disease. We concluded that false-negative 123I-MIBG SPECT is frequently related to metastatic tumors and usually due to SDHB mutations with unfavorable prognosis. We therefore recommend that patients with false-negative 123I-MIBG SPECT be tested for SDHB mutations and undergo more regular and close follow-up.
Introduction
Pheochromocytoma (PHEO) and paragangliomas (PGLs) are tumors arising from chromaffin cells of the adrenal medulla or extraadrenal paraganglionic tissues respectively (DeLellis et al. 2004). These tumors express the cellular membrane norepinephrine transporter (NET), through which catecholamines can enter and be deposited into neurosecretory granules via vesicular monoamine transporter systems (VMATs). Metaiodobenzylguanidine (MIBG) is a guanethidine analogue resembling norepinephrine (NE) that can enter chromaffin cells through active uptake via NET or passive diffusion and is stored in catecholamine-containing neurosecretory granules (Sisson et al. 1981, Bomanji et al. 1987, Havekes et al. 2008, Vaidyanathan 2008). This characteristic makes MIBG very useful and extremely specific for the diagnostic localization of PHEO and PGL when labeled with radiotracers such as iodine-123 (123I) or iodine-131 (131I) (Sisson et al. 1981, Ilias & Pacak 2004, Havekes et al. 2008, Goldsmith 2009, Timmers et al. 2009a,b, Jacobson et al. 2010, Meyer-Rochow et al. 2010). In addition, 131I-MIBG is also used for the treatment of metastatic PHEOs and PGLs that demonstrate avid MIBG uptake (Loh et al. 1997, Rose et al. 2003, Gonias et al. 2009, Castellani et al. 2010).
It was previously shown that 123/131I-MIBG scintigraphy has a sensitivity of about 78% in the detection of primary, sporadic, and nonmetastatic PHEO and PGL, which is comparable with other nuclear imaging studies such as 2-[18F]-fluoro-2-deoxy-d-glucose (18F-FDG), [18F]-fluorodopamine (18F-FDA), and [18F]-fluorodopa (18F-DOPA) positron emission tomography (PET) that have sensitivities of 78–88% (Timmers et al. 2009a,b). However, the sensitivity of 123/131I-MIBG scintigraphy in the detection of metastatic tumors and familial PHEO and PGL is about 53–60.9%, which is somewhat suboptimal compared to other nuclear imaging studies (Shulkin et al. 1999, van der Harst et al. 2001, Ilias et al. 2003, Taïeb et al. 2004, Fiebrich et al. 2009, Goldsmith 2009, Kauhanen et al. 2009, Fottner et al. 2010). It is also less sensitive in the detection of extraadrenal and small PHEO and PGL (van der Harst et al. 2001, Bhatia et al. 2008, Wiseman et al. 2009). The uptake of MIBG was also shown to be well correlated with the presence of NET or VMATs (Bomanji et al. 1987, Eisenhofer 2001, Fottner et al. 2010). Thus, the number of neurosecretory granules and perhaps the degree of differentiation of tumor cells controlling the expression of NET may play an important role in a successful application of 123/131I-MIBG scintigraphy. Nevertheless, 123/131I-MIBG scintigraphy remains widely used because it is readily available and less expensive than 18F-FDA PET/computed tomography (CT) and 18F-FDOPA PET.
Initially, we observed that patients with PHEO and PGL, especially those growing rapidly, presented with false-negative 123I-MIBG single photon emission computed tomography (SPECT). Some of these false-negative results were found to be associated with succinate dehydrogenase subunit B (SDHB) gene mutations. Therefore, we hypothesized that false-negative 123I-MIBG SPECT in patients having either primary, recurrent, or metastatic disease would point toward the presence of SDHB mutations. Proving this hypothesis would alert physicians to initiate SDHB mutation testing in these patients, especially among those who have negative family history of this disease. Furthermore, we hypothesized that these 123I-MIBG SPECT-negative tumors could reflect more aggressive behavior (as also commonly seen in SDHB patients) and should also alert physicians to perform more regular follow-up, including biochemical and imaging tests.
Materials and methods
Patients
Official results of 123I-MIBG SPECT of patients seen at the National Institutes of Health (NIH) from 2002 through March 2011 for evaluation of PHEO and PGL were reviewed. Patients with false-negative 123I-MIBG SPECT at any point from initial presentation to follow-up were identified and included in the present study if they were diagnosed with PHEO and PGL based on clinical presentation, specific biochemical tests (including measurement of catecholamine and metanephrines (MNs) in either plasma or urine), PHEO- and PGL-specific imaging studies, and histopathological confirmation of resected tumors. All patients were part of an Institutional Review Board-approved prospective study of patients with known or suspected PHEO and/or PGL at NIH. All patients provided informed consent.
Biochemical tests
Patients were asked to abstain from acetaminophen for 5 days and caffeinated and decaffeinated products, smoking, and alcohol for 24 h prior to blood extraction and 24-h urine collection. For plasma catecholamine and MN determination, a cannula was inserted in the forearm for i.v. access. Patients rested in the supine position without a pillow in a quiet room for 20–30 min before and during collection. As soon as blood was collected, it was placed on ice and stored at −80 °C until testing. Basal plasma levels of catecholamines and MNs were measured by HPLC. For urinary catecholamine and MN determination, total volume collected over 24 h was used and measured by HPLC or liquid chromatography–tandem mass spectrometry. Hypersecretion of plasma or urinary catecholamines or MNs was defined as any elevation above the upper reference limit.
Imaging tests
Computed tomography
Axial images of the neck, chest, abdomen, and pelvis were obtained after administration of oral and i.v. low-osmolar contrast. Multiple helical axial images at 2.5 and 5 mm thick were obtained in the neck and from the thoracic inlet to the symphysis pubis respectively.
Magnetic resonance imaging
Axial images of the head, neck, chest, abdomen, and pelvis were obtained. Axial T1, axial short time inversion recovery (STIR), and postcontrast fat-saturated axial T1-weighted images were obtained through the neck, while T1- and T2-weighted scans and STIR images were obtained in the chest. Scans were obtained before, during, and after i.v. injection of 14 ml Magnevist. In the abdomen, multiple sequences including axial T2-weighted (one without fat suppression with respiratory trigger; another one with fat suppression and suspended respiration) and two dimensional (2D) in- and out-of-phase T1-weighted images prior to, and multiphase three dimensional (3D) volume images in axial planes, single venous coronal following vascular contrast administration (18 cc Magnevist) were obtained at 3 T. If clinically indicated, magnetic resonance imaging (MRI) of the spine was obtained with sagittal T1-weighted and sagittal STIR images of the cervical, thoracic, and lumbar spine without administration of contrast material. Axial T2-weighted images were acquired at selected levels.
123I-MIBG SPECT
Patients were required to discontinue medications that could potentially interfere with MIBG uptake (e.g. labetalol, monoamine oxidase inhibitors, phenylpropanolamine, tricyclic, and other antidepressants, or reserpine) at least 1 week before the procedure. To protect the thyroid from accumulation of free radioactive iodine, patients received 100 mg of saturated solution of potassium iodide by mouth twice a day for 4 days starting the night before 123I-MIBG administration. Whole body planar and SPECT imaging were done in most cases 24 h, and in some 48 h, after i.v. administration of 8.4–11 mCi (mean: 10.18) 123I-MIBG. Attenuation CT scans were available for three patients.
Other functional imaging studies
18F-FDG PET/CT, 18F-FDA PET/CT, and 18F-FDOPA PET were performed. The patients were asked to fast for at least 6 h prior to i.v. injection of 18F-FDA (1 mCi), 18F-FDG (15.9 mCi), and 18F-FDOPA (12 mCi). Patients were also asked to refrain from caffeine, tobacco, and alcohol for at least 12 h. Capillary blood glucose was measured before 18F-FDG PET/CT. A low-dose, noncontrast, nondiagnostic CT was obtained for attenuation correction and anatomic localization. For 18F-FDOPA PET, patients received 2 mg/kg carbidopa orally as pretreatment 1 h before radiotracer injection.
Genetic testing
Genetic testing was performed at the Department of Human Genetics of the Pittsburgh University Medical Center Clinic, Pennsylvania, and at Mayo Clinic Laboratories, Minnesota, USA. A stepwise approach to genetic testing was performed based on the most likely gene mutation based on the clinical presentation, biochemical phenotype, and the location of tumor(s). Patients were tested for von Hippel–Lindau, MEN2, SDHB, and SDHC and SDHD gene mutations (Maher & Eng 2002). Not all currently known susceptibility genes for PHEO and PGL were tested in our patients if a specific gene mutation causing the disease was already found. Furthermore, testing for TMEM127, SDHA, SDHAF2, and MAX gene mutations was not performed (Comino-Méndez et al. 2011, Hensen & Bayley 2011).
Statistical analysis
123I-MIBG studies were reviewed separately by two experienced nuclear medicine physicians (C C and J R) who were blinded to any anatomic imaging studies and clinical history of patients. Physiologic uptake in the adrenal gland was carefully distinguished from abnormal uptake using the widely accepted four-point visual scale: (0) no increased activity demonstrated in one or both adrenal glands; (1) faint increased activity demonstrated in one or both adrenal glands; (2) moderate increased activity in one or both adrenal glands less than or equal to that of the liver; and (3) intense increased activity in one or both adrenal glands greater than the liver. Scores of 0–2 were classified as negative or physiologic uptake, while a score of 3 was classified as positive for PHEO or PGL.
All patients with adrenal tumors had histopathological confirmation of PHEO. Thus, a false-negative 123I-MIBG scan among these patients was defined as the absence of uptake or radiotracer uptake in the adrenal gland less than that of the liver (score 0–2). On the other hand, patients with multiple metastatic lesions or inoperable tumors may not have pathologic confirmation of metastatic PHEO or PGL. Therefore, a false-negative 123I-MIBG scan in this group was defined as the absence of radiotracer uptake in a tumor of a patient who had clinical, biochemical, and anatomical and specific nuclear imaging studies clearly consistent with PHEO and PGL.
Metastatic PHEO or PGL was defined as the presence of tumors at sites where chromaffin tissues, such as the bones, liver, lungs, and lymph nodes, are not normally located. Multifocal disease was defined as the presence of multiple tumor foci, presenting synchronously or metasynchronously (new primary) to the original tumor, whereas recurrence was defined as reappearance of the disease as documented at reintervention or by combined biochemical and radiological tests after previous complete eradication of the tumor.
Results
Patient characteristics
Of the 245 patients who underwent 123I-MIBG SPECT, we identified 21 patients (7 males, 14 females) aged 13–55 years (mean: 41.40 years) with false-negative 123I-MIBG SPECT. Seven of these patients were referred for evaluation and management of possible PHEO and PGL, while the remaining 14 patients were referred after previous surgery of their primary tumor (adrenal PHEO, n=4; urinary bladder PGL, n=3; retroperitoneal and extraadrenal PGL, n=6; and carotid body tumor, n=1) (Table 1). After a thorough evaluation, eight patients were found to have nonmetastatic tumors and thirteen were found to have metastatic disease.
Characteristics of patients at the time of false-negative 123I-MIBG SPECT
| Hypersecretion in plasma | Hypersecretion in urine | ||||||
|---|---|---|---|---|---|---|---|
| Patient | Age (years)/sex | Reason for consult at NIH | Metanephrines | Catecholamines | Metanephrines | Catecholamines | Gene mutation |
| 1 | 13/F | P | NMN, MN | NE, E, DA | – | – | Apparently sporadic |
| 2 | 47/F | P | NMN, MN | E | NMN, MN, T | None | RET |
| 3 | 51/F | P | NMN, MN | NE, E | NMN, MN, T | NE, E | Apparently sporadic |
| 4 | 61/M | P | None | DA | – | – | SDHB |
| 5 | 49/F | P | NMN | NE | NMN, T | NE | Apparently sporadic |
| 6 | 46/F | P | NMN, MN | None | – | – | Apparently sporadic |
| 7 | 36/F | New P | NMN | NE | NMN, T | NE | SDHB |
| 8 | 40/F | R | NMN | NE | NMN, T | NE, DA | Apparently sporadic |
| 9 | 55/M | Met+New P | NMN | NE, DA | NMN, T | NE | Neg for SDHx |
| 10 | 54/M | Met+New P | NMN | NE, DA | NMN, T | NE, DA | SDHB |
| 11 | 42/F | Met+New P | NMN | NE, DA | NMN, T | NE | SDHB |
| 12 | 36/F | Met | NMN | NE | NMN, T | NE | SDHB |
| 13 | 32/M | Met | NMN, MN | None | None | None | Apparently sporadic |
| 14 | 47/F | Met | None | None | – | – | SDHB |
| 15 | 43/F | Met | NMN | NMN | NMN, T | None | SDHB |
| 16 | 34/M | Met | NMN | NE, DA | – | – | SDHB |
| 17 | 37/M | Met | NMN | NE, DA | – | – | SDHB |
| 18 | 43/F | Met | None | None | – | – | SDHB |
| 19 | 45/F | Met | NMN | NE | None | NE | Apparently sporadic |
| 20 | 33/M | Met | None | None | – | – | SDHB |
| 21 | 22/F | Met | NMN | NE | NMN, T | NE | Apparently sporadic |
Adr, adrenal gland; DA, dopamine; E, epinephrine; F, female; M, male; Met, metastasis; MN, metanephrine; NE, norepinephrine; Neg, Negative; NMN, normetanephrine; P, primary tumor; R, recurrence; RET, rearranged during transfection; SDHB, succinate dehydrogenase subunit B; SDHD, succinate dehydrogenase subunit D; T, total metanephrines; –, not available.
Plasma MNs were elevated in 17 patients (81%) (5 had both normetanephrine (NMN) and MN elevated, 12 had elevated NMN only), while 4 had normal levels. Plasma catecholamines were elevated in 15 patients (71%) (one had elevated NE, epinephrine (EPI), and dopamine (DA); one had elevated NE and EPI; five had elevated NE and DA; six had elevated NE only; one had elevated EPI only; and one had elevated DA only). Urinary MNs and catecholamines were available only in 13 patients. Eleven patients (85%) had elevated urinary MNs (two had elevated total MNs, NMN, and MN; nine had elevated total MNs and NMN). Ten patients (83%) had elevated urinary catecholamines (one had elevated NE and EPI; two had elevated NE and DA; and seven had elevated NE only).
Results of anatomical and functional imaging studies are presented in Table 2. All patients had tumors (primary or metastatic) that failed to accumulate 123I-MIBG at first presentation to NIH, except patients nos 11, 15, 18, and 19, in whom false-negative scans were observed on follow-up (second 123I-MIBG SPECT) when they developed metastatic disease (patient no. 18) or progression of known metastatic disease (patients nos 11, 15, and 19). Of the eight patients with nonmetastatic tumors (patients nos 1–8), anatomical and nuclear imaging studies other than 123I-MIBG SPECT/CT showed adrenal gland PHEO (n=6; five unilateral, one bilateral), paraesophageal PGL (n=1), and paraaortic PGL (n=1), which were confirmed by histopathology after surgery. In patient no. 2 with MEN2 syndrome, 18F-FDG PET/CT further showed increased uptake of radiotracer in the skull, neck, and mediastinum, which was proven to be related to medullary tumor of the thyroid gland after excision. None of them were found to have multifocal or metastatic disease, as proven by multiple imaging studies, together with normalization of plasma MNs and catecholamines postoperatively.
Comparative imaging studies of patients with false-negative 123I-MIBG SPECT
| Patient | CT | MRI | 123I-MIBG | 18F-FDA | 18F-FDOPA | 18F-FDG-PET |
|---|---|---|---|---|---|---|
| 1 | R adr | NA | Neg | NA | NA | R adr |
| 2 | R+L adr | R+L adr | Neg | Neg | NA | R parietal skulla, R upper posterior necka, R mediastinuma |
| 3 | L adr | L adr | Neg | L adr | NA | L adr |
| 4 | L paraaortic, L renal massb | L paraaortic | Neg | Neg | Neg | L paraaortic, and L kidney |
| 5 | R adr | R adr | Neg | R adr | NA | NAc |
| 6 | R+L adr | R+L adr | Neg | Neg | R adr | NA |
| 7 | Paraesophageal | Paraesophageal | Normal adr uptake | Neg | NA | Paraesophageal |
| 8 | R adr | NA | Neg | Neg | NA | Neg |
| 9 | Liver, lung, LN, B, bilateral carotid | Liver, LN, B, bilateral carotid | Neg | B | B, liver, LN | R carotid, soft tissues adjacent to C2 and C3 cervical vertebrae, B, liver, LN |
| 10 | B, LN, lungs, R adr | NA | Normal adr uptake | LN | NA | NA |
| 11 | B, lungs, liver, periaortic | R adr, B, liver, retroperitoneal L periaortic | Normal adr uptake | Liver, B, LN, soft tissues in the abdomen | NA | B, L upper abdomen in the region of the pancreas and toward the L side of the upper abdomen, liver, LN and soft tissues in the abdomen |
| 12 | Lung, pelvic LN | Lung, pelvic LN | Normal adr uptake | Neg | NA | Lungs, pelvic LNd |
| 13 | B | B | Normal adr uptake | B | NA | B |
| 14 | Lung, LN, B | Be | Normal adr uptake | Neg | Neg | B, lungs |
| 15 | B, liver, LN, Infrasplenic | B, liver, LN | Normal adr uptake | B, infrasplenic | NA | R posterior medial lung, B, L lateral abdomen, liver |
| 16 | B, lungs, LN, liver, L paraaortic mass, intrathoracic prevertebral mass | B, liver, LN, L paraaortic mass, intrathoracic prevertebral masse | Normal adr uptake | Neg | NA | Lungs, LN, B, liver, L lower abdomen extending to the midline |
| 17 | LN, lungs, B, liver | B, LN, liver | Normal adr uptake | LN | Neg | LN, B, liver |
| 18 | LN | LN | Normal adr uptake | Neg | NA | B, LN |
| 19 | Lungs, LN | Lungs, LN | Normal adr uptake | R mediastinum at the hilar area, L lung, LN | NA | Lungs, LN |
| 20 | R carotid LN in the chest | R carotid LN in the chest | Neg | Neg | R carotid | LN in the chest |
| 21 | LN | LN | Normal adr uptake | LN | LN | LN |
Adr, adrenal gland; B, bones; L, left; LN, lymph nodes; NA, not available; Neg, negative; R, right; 18F-FDA, 18F-fluorodopamine; 18F-FDOPA, 18F-dihydroxyphenylalanine; 18F-FDG PET, 2-[18F]-fluoro-2-deoxy-d-glucose positron emission tomography. Normal adr uptake means a score of 1–2 and was considered to be physiologic uptake in the adrenal gland.
Medullary thyroid cancer-related.
Left renal mass: renal cell carcinoma by histopathology.
Available from outside prior to referral to NIH with increased uptake in the right adrenal gland.
Outside scan not available for review.
MRI of the chest not done.
Among the 13 patients with metastatic disease, metastases were noted in the lungs (n=8), multiple bony sites (n=9), lymph nodes (n=12), liver (n=5), and other soft tissues (n=3). Despite multiple tumor sites found per patient, none showed avid 123I-MIBG uptake. Patient no. 10 with metastatic disease was concomitantly found to have another primary tumor in the right adrenal gland, while patient no. 9 developed additional primary tumors bilaterally in the carotid bodies with metastatic disease in the liver, lungs, lymph nodes, and bones, as shown in Fig. 1, after removal of a urinary bladder PGL. In these patients, both the primary and metastatic tumors had no uptake of 123I-MIBG.
Nuclear imaging studies of a 55-year old male with metastatic pheochromocytoma who tested negative for succinate dehydrogenase B, C, and D mutations. The primary tumor was found in the urinary bladder and was removed with en bloc cystectomy, prostatectomy, with lymphatic node dissection and creation of ileal neobladder in 2005. In 2009, he was diagnosed with metastatic disease with false-negative 123I-MIBG SPECT/CT. At NIH, (A) 123I-MIBG SPECT/CT was also negative, but other nuclear imaging such as (B) 18F-FDA, (C) 18F-FDOPA, and especially (D) 18F-FDG PET showed multiple metastatic foci in the lymph nodes, lungs, and liver. He underwent radiofrequency ablation of liver lesions. A repeat 18F-FDG PET/CT after 3 months showed evidence of progression.
Citation: Endocrine-Related Cancer 19, 1; 10.1530/ERC-11-0243
Of the seven patients with adrenal PHEO (five primary and nonmetastatic; one recurrence; and one new primary with metastases), the mean largest diameter of the tumor was 4.3 cm (range: 1.5–7 cm). In one patient with a primary tumor in the right carotid body and in another patient with a left paraaortic PGL, the tumors measured 0.8 and 1.5 cm respectively.
Eleven (52%) patients were found to have an SDHB mutation and one (4%) was found to have MEN2 syndrome, while the remaining patients presented with apparently sporadic PHEO and/or PGL. Among SDHB-related tumors, nine were associated with metastatic disease, one had multifocal tumors, and one had a nonmetastatic tumor.
Outcome analysis
Patients with false-negative 123I-MIBG SPECT performed before 2008 were included for outcome analysis (n=19). Five patients were excluded due to lack of follow-up (n=4) and infection with human immunodeficiency virus (n=1). A total of 14 cases were analyzed with a mean follow-up period of 5 years (range: 2–7) after the first documented false-negative 123I-MIBG SPECT at NIH (Table 3). On initial presentation at NIH, four (29%) of these patients had no metastases, while ten (71%) had metastatic disease.
Outcome of patients with false-negative 123I-MIBG SPECT
| Living | Dead | |
|---|---|---|
| n | 9 | 5 |
| Tumor type | ||
| Nonmetastatic | 4 | 0 |
| Metastatic | 5 | 5 |
| Primary tumor location | ||
| Adrenal | 2 | 2 |
| Extraadrenal | 7 | 3 |
| Gene mutation | ||
| SDHB | 5 | 4 |
| Sporadic | 4 | 1 |
Of the four patients with nonmetastatic PHEO or PGL, none developed metastatic disease until March 2011, when one patient (patient no. 7) developed another primary tumor in the left carotid body and a paraesophageal PGL about 6 years after a false-negative 123I MIBG SPECT. Two of the nonmetastatic cases were due to SDHB mutations, while the other two were apparently sporadic. All the patients are still alive.
Of the ten patients with metastatic disease, nine (90%) had SBHB mutations, while the remaining case had apparently sporadic PHEO or PGL. Patient no. 12 had multiple metastases in the lungs and left paraaortic lymph nodes, which were excised. Patient no. 15 had multiple metastases to the bones, liver, and lymph nodes and was given chemotherapy with cyclophosphamide+vincristine+dacarbazine (CVD), sunitinib, bortezomib, 17-DMAG, and external beam radiotherapy. Patient no. 16 who had multiple metastases to the bones, lungs, liver, and lymph nodes received chemotherapy with CVD and underwent radiofrequency ablation of liver metastases. Patients nos 11 and 17 who had metastases to the bones, liver, lungs, and lymph nodes were treated with CVD and 17-DMAG respectively. Patient no. 18 had gamma knife radiotherapy of a carotid body tumor invading the skull, which was later resected. She also received CVD chemotherapy. Patient no. 19 developed metastatic lesions with avid uptake on subsequent 123I-MIBG SPECT and therefore underwent 131I-MIBG treatment, but due to persistent disease, she also received temozolomide. Patient no. 21 had resection of the periaortic lymph node and hilar metastases and developed another primary tumor in the left adrenal gland 6 years after the initial diagnosis, which was also resected. Five (55%) (four SDHB+one sporadic) died due to overwhelming metastases after a mean of 10.4 years (range: 3–17 years) after the initial diagnosis of PHEO or PGL and a mean of 5.2 years (range: 3–7 years) after development of metastatic disease. Sixty percent of deaths occurred within 5 years of the diagnosis of metastatic disease. Four other patients (two SDHB and two sporadic) had progressive disease within a mean follow-up of 7.25 years (range: 6–9 years), while one other patient had stable metastatic disease.
Discussion
The present study shows detailed characteristics and outcomes of patients with false-negative 123I-MIBG SPECT. The majority had primary tumors of extraadrenal chromaffin tissues, noradrenergic biochemical phenotype, and metastases, and over half had mutations in SDHB. The latter comprise 25 and 69% of patients with nonmetastatic and metastatic PHEO or PGL respectively. To our best knowledge, this is the first paper to show that PHEOs or PGLs in patients with false-negative 123I-MIBG SPECT follow a more aggressive course and are frequently linked to the presence of SDHB mutations.
In general, it is estimated that the rate of malignancy among patients with PHEO and PGL is about 10–30%, and that ∼10% have metastatic disease upon initial presentation (Goldstein et al. 1999). It is also estimated that at least one-third of PHEOs and PGLs have a defined genetic cause (Amar et al. 2005, Erlic et al. 2009, Mannelli et al. 2009). However, we have shown in the present study that among patients with false-negative 123I-MIBG SPECT, the rate of malignancy was higher, at 62% (13 out of 21), and 24% (5 out of 21) had metastatic disease on initial presentation. Furthermore, 57% (12 out of 21) were due to a genetic mutation, with 92% (11 out of 12) of these cases linked to SDHB mutations.
It is well established that PHEO or PGL due to SDHB mutations is associated with shorter survival (Amar et al. 2007) and higher incidence of malignancy (Brouwers et al. 2006, Burnichon et al. 2009, Timmers et al. 2009a,b). It is estimated that the malignancy rate of SDHB-related PHEO or PGL is at least 30% and often much higher; the 5-year probability of survival after the diagnosis of first metastasis among these patients drops to 36%, in contrast to 67% among patients without SDHB mutations (Amar et al. 2007). In our study, SDHB mutations accounted for 69% of metastatic disease and 80% of mortality. In the present study, 44% (four out of nine) of patients with apparently sporadic PHEO and PGL were found to have metastatic disease, resulting in death of one patient within 6 years of the diagnosis of metastasis. In contrast to these data, it was previously shown that the rate of malignancy among apparently sporadic tumors is only 9% (Bravo & Tagle 2003). It should be further emphasized that of the five patients who had metastatic disease upon initial diagnosis, three had apparently sporadic tumors. These results suggest that negative 123I-MIBG SPECT points toward an unfavorable outcome that may be independent of SDHB mutations. Thus, patients with false-negative 123I-MIBG SPECT should be tested for SDHB mutations because a larger percentage of patients, as shown in this paper, harbor SDHB mutations. Screening for SDHB mutations is important not only because it is independently associated with higher rates of malignancy and mortality, but also because it allows for the identification of family members with the mutation for early diagnosis and treatment. Furthermore, it will guide clinicians in terms of which treatment to use, with CVD being the treatment of choice for SDHB-related metastatic disease (unpublished observations); which biochemical markers to use in the follow-up, with plasma methoxytyramine as the preferred test (Eisenhofer et al. 2011); and lastly, the imaging test of choice, with 18F-FDG PET/CT having the highest sensitivity in detecting metastatic tumors (Timmers et al. 2007a,b).
There are several factors that can cause a false-negative 123I-MIBG study. Medications such as labetalol, reserpine, calcium channel blockers, and antidepressants may interfere with MIBG uptake (Solanki et al. 1992, Havekes et al. 2008). 123/131I-MIBG scintigraphy has been shown to have lower sensitivity for small tumors (van der Harst et al. 2001, Bhatia et al. 2008, Wiseman et al. 2009). However, two of our patients had adrenal PHEOs measuring 7 cm with false-negative scans by 123I-MIBG SPECT. The sensitivity of 123/131I-MIBG scintigraphy is also generally suboptimal for extraadrenal PGLs; this was demonstrated in the present study by the inclusion of a patient with a mediastinal PGL measuring 8 cm with a false-negative 123I-MIBG SPECT. The suboptimal sensitivity of 123/131I-MIBG for metastatic PHEO and PGL has also been shown in previous studies and is related to the dedifferentiation that results in loss of NET among these tumors (Ilias et al. 2003, Timmers et al. 2009a,b). The limited sensitivity of 123/131I-MIBG scintigraphy for familial cases of PHEO and PGL has also been documented (van der Harst et al. 2001, Ilias et al. 2003, Taïeb et al. 2004, Bhatia et al. 2008, Timmers et al. 2009a,b, Fottner et al. 2010). Thus, 123I-MIBG scintigraphy is not recommended for these patients and negativity may reflect aggressive behavior. Studies have also shown that a predominantly NE and NMN secretion predicts negative 123I-MIBG scintigraphy that was also observed in our study (van der Harst et al. 2001, Fottner et al. 2010). However, only 81% of our patients had elevated plasma NMN, which is known to have a sensitivity of about 97–99% in detecting PHEO and PGL in general (Lenders et al. 2002, Sawka et al. 2003). This may be due to the fact that the majority of our patients had SDHB-related tumors, and it was previously demonstrated that plasma NMN was elevated in only about 82% of patients with SDHB mutations (Timmers et al. 2007a,b). These results raise important questions whether other biochemical markers, including chromogranin A and plasma methoxytyramine, could be of a diagnostic value in these patients, in whom early diagnosis and treatment is paramount. However, one study showed that the uptake of MIBG was not correlated with plasma or urinary catecholamine levels, but with the amount of neurosecretory granules within the tumor (Bomanji et al. 1987). Recently, it was shown that VMAT-1 expression is lacking in a cohort of patients with false-negative MIBG scintigraphy, the majority of whom had familiar PHEOs or PGLs, with two patients having SDHB gene mutations (Fottner et al. 2010).
The evaluation of patients with biochemically proven PHEO or PGL commences with anatomical imaging studies, such as CT and MRI scans, followed by nuclear imaging studies. For patients with adrenal tumors <5 cm, especially those associated with increased MN or EPI, nuclear imaging studies may not be done because the likelihood of metastatic disease or multifocal tumors is low. In patients with adrenal tumors more than 5 cm, extraadrenal tumors, and those associated with increases in NMN and NE, nuclear imaging studies should be done to prove that the tumor is indeed PHEO or PGL and to look for possible metastatic or multifocal tumors. The role of 123I-MIBG SPECT in the evaluation of PHEO and PGL is currently debatable. Clearly, there is benefit for patients who will have to undergo 131I-MIBG treatment for metastatic tumors. However, it has a limited role in the localization of extraadrenal and metastatic tumors, and as shown in the present study, SDHB-related tumors. 18F-FDA PET/CT is the imaging technique of choice for extraadrenal primary tumors (Ilias et al. 2003), while 18F-FDOPA PET/CT is most optimal for head and neck PGL, especially SDHB- and SDHD-related tumors (Fiebrich et al. 2009, Fottner et al. 2010, King et al. 2011). For patients with metastatic disease, 18F-FDA PET/CT is the imaging technique of choice, especially for those with unknown gene mutations (Timmers et al. 2009a,b). However, for those related to SDHB, 18F-FDG PET/CT is the best imaging modality (Timmers et al. 2007a,b, 2009a,b). In centers where these imaging modalities are not available, patients who present with extraadrenal and possible metastatic tumors in anatomical imaging studies but have probable false-negative 123I-MIBG SPECT should be referred to specialty centers where 18F-FDA PET/CT, 18F-FDOPA PET, and 18F-FDG PET/CT are available. Testing for SDHB mutations should also be carried out, especially for patients with metastatic disease, and as observed in this study, may also be done in patients with nonmetastatic tumors with false-negative 123I-MIBG SPECT.
The present study has some limitations. Most patients who were referred to NIH due to metastatic disease did not have preoperative 123/131I-MIBG scintigraphy. Furthermore, the data may be affected by referral bias, and the follow-up period for some patients seen at NIH for their primary tumors was relatively short to definitively exclude nonmetastatic disease. It is also recommended that a head-to-head comparison be made of the outcomes of SDHB-related tumors with avid and false-negative 123I-MIBG SPECT. We also recommend a multicenter study to increase the number of patients to be evaluated with this rare disease of PHEO and PGL and in this even rarer subset of patients with false-negative 123I-MIBG SPECT.
In conclusion, we have shown that a false-negative 123I-MIBG SPECT is frequently related to metastatic tumors, usually due to SDHB mutations, with unfavorable prognosis. We therefore recommend that patients with false-negative 123I-MIBG SPECT be tested for SDHB mutations and undergo more regular and close follow-up.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This work was supported by the Intramural Research Program of the National Institute of Child Health and Human Development/National Institutes of Health.
Author contribution statement
All authors were involved in conceptualizing this research paper and contributed in the writing and editing of the final manuscript. Furthermore, J S Fonte, MD and J F Robles, MD were involved in data gathering. J S Fonte, MD, K Pacak, MD, PhD, DSc, C C Chen, MD, J Reynolds, MD, and M Whatley reviewed the nuclear imaging studies of the patients. J S Fonte, MD, K Pacak, MD, PhD, DSc, and A Ling, MD reviewed the CT scans and MRIs of the patients. K Pacak, MD, PhD, DSc, T Fojo, MD, K Adams, J S Fonte, MD, and J F Robles, MD were involved in the management of the patients included in the present study. J S Fonte, MD and K Pacak, MD, PhD, DSc wrote the initial manuscript.
Acknowledgements
J S Fonte, MD and J F Robles, MD acknowledge the staff of the Section of Endocrinology and Metabolism, Department of Medicine, University of Santo Tomas Hospital, Manila, Philippines; and Thomasian Endocrine Progress Inc. for their invaluable support during their training at the National Institutes of Health.
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