Henri Timmers

Superiority of Fluorodeoxyglucose Positron Emission Tomography to Other Functional Imaging Techniques in the Evaluation of Metastatic SDHB-Associated Pheochromocytoma and Paraganglioma

PURPOSE Germline mutations of the gene encoding subunit B of the mitochondrial enzyme succinate dehydrogenase (SDHB) predispose to malignant paraganglioma (PGL). Timely and accurate localization of these aggressive tumors is critical for guiding optimal treatment. Our aim is to evaluate the performance of functional imaging modalities in the detection of metastatic lesions of SDHB-associated PGL. PATIENTS AND METHODS Sensitivities for the detection of metastases were compared between [18F]fluorodopamine ([18F]FDA) and [18F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET), iodine-123- (123I) and iodine-131 (131I) -metaiodobenzylguanidine (MIBG), 111In-pentetreotide, and Tc-99m-methylene diphosphonate bone scintigraphy in 30 patients with SDHB-associated PGL. Computed tomography (CT) and magnetic resonance imaging (MRI) served as standards of reference. RESULTS Twenty-nine of 30 patients had metastatic lesions. In two patients, obvious metastatic lesions on functional imaging were missed by CT and MRI. Sensitivity according to patient/body region was 80%/65% for 123I-MIBG and 88%/70% for [18F]FDA-PET. False-negative results on 123I-MIBG scintigraphy and/or [18F]FDA-PET were not predicted by genotype or biochemical phenotype. [18F]FDG-PET yielded a by patient/by body region sensitivity of 100%/97%. At least 90% of regions that were false negative on 123I-MIBG scintigraphy or [18F]FDA-PET were detected by [18F]FDG-PET. In two patients, 111In-pentetreotide scintigraphy detected liver lesions that were negative on other functional imaging modalities. Sensitivities were similar before and after chemotherapy or 131I-MIBG treatment, except for a trend toward lower post- (60%/41%) versus pretreatment (80%/65%) sensitivity of 123I-MIBG scintigraphy. CONCLUSION With a sensitivity approaching 100%, [18F]FDG-PET is the preferred functional imaging modality for staging and treatment monitoring of SDHB-related metastatic PGL.

Comparison of 18F-Fluoro-L-DOPA, 18F-Fluoro-Deoxyglucose, and 18F-Fluorodopamine PET and 123I-MIBG Scintigraphy in the Localization of Pheochromocytoma and Paraganglioma

CONTEXT Besides (123)I-metaiodobenzylguanidine (MIBG), positron emission tomography (PET) agents are available for the localization of paraganglioma (PGL), including (18)F-3,4-dihydroxyphenylalanine (DOPA), (18)F-fluoro-2-deoxy-D-glucose ((18)F-FDG), and (18)F-fluorodopamine ((18)F-FDA). OBJECTIVE The objective of the study was to establish the optimal approach to the functional imaging of PGL and examine the link between genotype-specific tumor biology and imaging. DESIGN This was a prospective observational study. INTERVENTION There were no interventions. PATIENTS Fifty-two patients (28 males, 24 females, aged 46.8 +/- 14.2 yr): 20 with nonmetastatic PGL (11 adrenal), 28 with metastatic PGL (13 adrenal), and four in whom PGL was ruled out; 22 PGLs were of the succinate dehydrogenase subunit B (SDHB) genotype. MAIN OUTCOME MEASURES Sensitivity of (18)F-DOPA, (18)F-FDG, and (18)F-FDA PET, (123)I-MIBG scintigraphy, computed tomography (CT), and magnetic resonance imaging (MRI) for the localization of PGL were measured. RESULTS Sensitivities for localizing nonmetastatic PGL were 100% for CT and/or MRI, 81% for (18)F-DOPA PET, 88% for (18)F-FDG PET/CT, 78% for (18)F-FDA PET/CT, and 78% for (123)I-MIBG scintigraphy. For metastatic PGL, sensitivity in reference to CT/MRI was 45% for (18)F-DOPA PET, 74% for (18)F-FDG PET/CT, 76% for (18)F-FDA PET/CT, and 57% for (123)I-MIBG scintigraphy. In patients with SDHB metastatic PGL, (18)F-FDA and (18)F-FDG have a higher sensitivity (82 and 83%) than (123)I-MIBG (57%) and (18)F-DOPA (20%). CONCLUSIONS (18)F-FDA PET/CT is the preferred technique for the localization of the primary PGL and to rule out metastases. Second best, equal alternatives are (18)F-DOPA PET and (123)I-MIBG scintigraphy. For patients with known metastatic PGL, we recommend (18)F-FDA PET in patients with an unknown genotype, (18)F-FDG or (18)F-FDA PET in SDHB mutation carriers, and (18)F-DOPA or (18)F-FDA PET in non-SDHB patients.

SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma

BACKGROUND Paragangliomas and phaeochromocytomas are neuroendocrine tumours associated frequently with germline mutations of SDHD, SDHC, and SDHB. Previous studies have shown the imprinted SDHAF2 gene to be mutated in a large Dutch kindred with paragangliomas. We aimed to identify SDHAF2 mutation carriers, assess the clinical genetic significance of SDHAF2, and describe the associated clinical phenotype. METHODS We undertook a multicentre study in Spain and The Netherlands in 443 apparently sporadic patients with paragangliomas and phaeochromocytomas who did not have mutations in SDHD, SDHC, or SDHB. We analysed DNA of 315 patients for germline mutations of SDHAF2; a subset (n=200) was investigated for gross gene deletions. DNA from a group of 128 tumours was studied for somatic mutations. We also examined a Spanish family with head and neck paragangliomas with a young age of onset for the presence of SDHAF2 mutations, undertook haplotype analysis in this kindred, and assessed their clinical phenotype. FINDINGS We did not identify any germline or somatic mutations of SDHAF2, and no gross gene deletions were noted in the subset of apparently sporadic patients analysed. Investigation of the Spanish family identified a pathogenic germline DNA mutation of SDHAF2, 232G-->A (Gly78Arg), identical to the Dutch kindred. INTERPRETATION SDHAF2 mutations do not have an important role in phaeochromocytoma and are rare in head and neck paraganglioma. Identification of a second family with the Gly78Arg mutation suggests that this is a crucial residue for the function of SDHAF2. We conclude that SDHAF2 mutation analysis is justified in very young patients with isolated head and neck paraganglioma without mutations in SDHD, SDHC, or SDHB, and in individuals with familial antecedents who are negative for mutations in all other risk genes. FUNDING Dutch Cancer Society, European Union 6th Framework Program, Fondo Investigaciones Sanitarias, Fundación Mutua Madrileña, and Red Temática de Investigación Cooperativa en Cáncer.

Measurements of plasma methoxytyramine, normetanephrine, and metanephrine as discriminators of different hereditary forms of pheochromocytoma.

BACKGROUND Pheochromocytomas are rare catecholamine-producing tumors derived in more than 30% of cases from mutations in 9 tumor-susceptibility genes identified to date, including von Hippel-Lindau tumor suppressor (VHL); succinate dehydrogenase complex, subunit B, iron sulfur (Ip) (SDHB); and succinate dehydrogenase complex, subunit D, integral membrane protein (SDHD). Testing of multiple genes is often undertaken at considerable expense before a mutation is detected. This study assessed whether measurements of plasma metanephrine, normetanephrine, and methoxytyramine, the O-methylated metabolites of catecholamines, might help to distinguish different hereditary forms of the tumor. METHODS Plasma concentrations of O-methylated metabolites were measured by liquid chromatography with electrochemical detection in 173 patients with pheochromocytoma, including 38 with multiple endocrine neoplasia type 2 (MEN 2), 10 with neurofibromatosis type 1 (NF1), 66 with von Hippel-Lindau (VHL) syndrome, and 59 with mutations of SDHB or SDHD. RESULTS In contrast to patients with VHL, SDHB, and SDHD mutations, all patients with MEN 2 and NF1 presented with tumors characterized by increased plasma concentrations of metanephrine (indicating epinephrine production). VHL patients usually showed solitary increases in normetanephrine (indicating norepinephrine production), whereas additional or solitary increases in methoxytyramine (indicating dopamine production) characterized 70% of patients with SDHB and SDHD mutations. Patients with NF1 and MEN 2 could be discriminated from those with VHL, SDHB, and SDHD gene mutations in 99% of cases by the combination of normetanephrine and metanephrine. Measurements of plasma methoxytyramine discriminated patients with SDHB and SDHD mutations from those with VHL mutations in an additional 78% of cases. CONCLUSIONS The distinct patterns of plasma catecholamine O-methylated metabolites in patients with hereditary pheochromocytoma provide an easily used tool to guide cost-effective genotyping of underlying disease-causing mutations.

MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma.

Purpose: Pheochromocytomas (PCC) and paragangliomas (PGL) are genetically heterogeneous neural crest–derived neoplasms. Recently we identified germline mutations in a new tumor suppressor susceptibility gene, MAX (MYC-associated factor X), which predisposes carriers to PCC. How MAX mutations contribute to PCC/PGL and associated phenotypes remain unclear. This study aimed to examine the prevalence and associated phenotypic features of germline and somatic MAX mutations in PCC/PGL. Design: We sequenced MAX in 1,694 patients with PCC or PGL (without mutations in other major susceptibility genes) from 17 independent referral centers. We screened for large deletions/duplications in 1,535 patients using a multiplex PCR-based method. Somatic mutations were searched for in tumors from an additional 245 patients. The frequency and type of MAX mutation was assessed overall and by clinical characteristics. Results: Sixteen MAX pathogenic mutations were identified in 23 index patients. All had adrenal tumors, including 13 bilateral or multiple PCCs within the same gland (P < 0.001), 15.8% developed additional tumors at thoracoabdominal sites, and 37% had familial antecedents. Age at diagnosis was lower (P = 0.001) in MAX mutation carriers compared with nonmutated cases. Two patients (10.5%) developed metastatic disease. A mutation affecting MAX was found in five tumors, four of them confirmed as somatic (1.65%). MAX tumors were characterized by substantial increases in normetanephrine, associated with normal or minor increases in metanephrine. Conclusions: Germline mutations in MAX are responsible for 1.12% of PCC/PGL in patients without evidence of other known mutations and should be considered in the genetic work-up of these patients. Clin Cancer Res; 18(10); 2828–37. ©2012 AACR.

Staging and Functional Characterization of Pheochromocytoma and Paraganglioma by 18F-Fluorodeoxyglucose (18F-FDG) Positron Emission Tomography

BACKGROUND Pheochromocytomas and paragangliomas (PPGLs) are rare tumors of the adrenal medulla and extra-adrenal sympathetic chromaffin tissues; their anatomical and functional imaging are critical to guiding treatment decisions. This study aimed to compare the sensitivity and specificity of (18)F-fluorodeoxyglucose positron emission tomography with computed tomography ((18)F-FDG PET/CT) for tumor localization and staging of PPGLs with that of conventional imaging by [(123)I]-metaiodobenzylguanidine single photon emission CT ((123)I-MIBG SPECT), CT, and magnetic resonance imaging (MRI). METHODS A total of 216 patients (106 men, 110 women, aged 45.2 ± 14.9 years) with suspected PPGL underwent CT or MRI, (18)F-FDG PET/CT, and (123)I-MIBG SPECT/CT. Sensitivity and specificity were measured as endpoints and compared by the McNemar test, using two-sided P values only. RESULTS Sixty (28%) of patients had nonmetastatic PPGL, 95 (44%) had metastatic PPGL, and 61 (28%) were PPGL negative. For nonmetastatic tumors, the sensitivity of (18)F-FDG was similar to that of (123)I-MIBG but less than that of CT/MRI (sensitivity of (18)F-FDG = 76.8%; of (123)I-MIBG = 75.0%; of CT/MRI = 95.7%; (18)F-FDG vs (123)I-MIBG: difference = 1.8%, 95% confidence interval [CI] = -14.8% to 14.8%, P = .210; (18)F-FDG vs CT/MRI: difference = 18.9%, 95% CI = 9.4% to 28.3%, P < .001). The specificity was 90.2% for (18)F-FDG, 91.8% for (123)I-MIBG, and 90.2% for CT/MRI. (18)F-FDG uptake was higher in succinate dehydrogenase complex- and von Hippel-Lindau syndrome-related tumors than in multiple endocrine neoplasia type 2 (MEN2) related tumors. For metastases, sensitivity was greater for (18)F-FDG and CT/MRI than for (123)I-MIBG (sensitivity of (18)F-FDG = 82.5%; of (123)I-MIBG = 50.0%; of CT/MRI = 74.4%; (18)F-FDG vs (123)I-MIBG: difference = 32.5%, 95% CI = 22.3% to 42.5%, P < .001; CT/MRI vs (123)I-MIBG: difference = 24.4%, 95% CI = 11.3% to 31.6%, P < .001). For bone metastases, (18)F-FDG was more sensitive than CT/MRI (sensitivity of (18)F-FDG = 93.7%; of CT/MRI = 76.7%; difference = 17.0%, 95% CI = 4.9% to 28.5%, P = .013). CONCLUSIONS Compared with (123)I-MIBG SPECT and CT/MRI, both considered gold standards for PPGL imaging, metastases were better detected by (18)F-FDG PET. (18)F-FDG PET provides a high specificity in patients with a biochemically established diagnosis of PPGL.

Plasma methoxytyramine: a novel biomarker of metastatic pheochromocytoma and paraganglioma in relation to established risk factors of tumour size, location and SDHB mutation status.

BACKGROUND There are currently no reliable biomarkers for malignant pheochromocytomas and paragangliomas (PPGLs). This study examined whether measurements of catecholamines and their metabolites might offer utility for this purpose. METHODS Subjects included 365 patients with PPGLs, including 105 with metastases, and a reference population of 846 without the tumour. Eighteen catecholamine-related analytes were examined in relation to tumour location, size and mutations of succinate dehydrogenase subunit B (SDHB). RESULTS Receiver-operating characteristic curves indicated that plasma methoxytyramine, the O-methylated metabolite of dopamine, provided the most accurate biomarker for discriminating patients with and without metastases. Plasma methoxytyramine was 4.7-fold higher in patients with than without metastases, a difference independent of tumour burden and the associated 1.6- to 1.8-fold higher concentrations of norepinephrine and normetanephrine. Increased plasma methoxytyramine was associated with SDHB mutations and extra-adrenal disease, but was also present in patients with metastases without SDHB mutations or those with metastases secondary to adrenal tumours. High risk of malignancy associated with SDHB mutations reflected large size and extra-adrenal locations of tumours, both independent predictors of metastatic disease. A plasma methoxytyramine above 0.2nmol/L or a tumour diameter above 5cm indicated increased likelihood of metastatic spread, particularly when associated with an extra-adrenal location. CONCLUSION Plasma methoxytyramine is a novel biomarker for metastatic PPGLs that together with SDHB mutation status, tumour size and location provide useful information to assess the likelihood of malignancy and manage affected patients.

EANM 2012 guidelines for radionuclide imaging of phaeochromocytoma and paraganglioma

PurposeRadionuclide imaging of phaeochromocytomas (PCCs) and paragangliomas (PGLs) involves various functional imaging techniques and approaches for accurate diagnosis, staging and tumour characterization. The purpose of the present guidelines is to assist nuclear medicine practitioners in performing, interpreting and reporting the results of the currently available SPECT and PET imaging approaches. These guidelines are intended to present information specifically adapted to European practice.MethodsGuidelines from related fields, issued by the European Association of Nuclear Medicine and the Society of Nuclear Medicine, were taken into consideration and are partially integrated within this text. The same was applied to the relevant literature, and the final result was discussed with leading experts involved in the management of patients with PCC/PGL. The information provided should be viewed in the context of local conditions, laws and regulations.ConclusionAlthough several radionuclide imaging modalities are considered herein, considerable focus is given to PET imaging which offers high sensitivity targeted molecular imaging approaches.

Denervation of Carotid Baro‐ and Chemoreceptors in Humans

Experimental denervation in animals has shown that carotid baro‐ and chemoreceptors play an eminent role in maintaining blood pressure and blood gas homeostasis. Denervation of carotid sinus baro‐ and chemoreceptors in humans may occur as a complication of invasive interventions on the neck or after experimental surgical treatment in asthma. In this topical review, the short‐ and long‐term effects of carotid baro‐ and chemoreceptor denervation on the control of circulation and ventilation in humans are discussed. Carotid baroreceptor denervation in humans causes a persistent decrease in vagal and sympathetic baroreflex sensitivity and an increase in blood pressure variability; however, carotid denervation does not lead to chronic hypertension. Therefore, although carotid baroreceptors contribute to short‐term blood pressure control, other receptors are able to maintain normal chronic blood pressure levels in the absence of carotid baroreceptors. Conversely, carotid chemoreceptor denervation leads to permanent abolition of normocapnic ventilatory responses to hypoxia and reduced ventilatory responses to hypercapnia.

The Effects of Carbidopa on Uptake of 6-18F-Fluoro-l-DOPA in PET of Pheochromocytoma and Extraadrenal Abdominal Paraganglioma

6-18F-fluoro-l-3,4-dihydroxyphenylalanine (18F-DOPA) PET is a useful tool for the detection of certain neuroendocrine tumors, especially with the preadministration of carbidopa, an inhibitor of DOPA decarboxylase. Whether carbidopa also improves 18F-DOPA PET of adrenal pheochromocytomas and extraadrenal paragangliomas is unknown. The aim of this study was to investigate the sensitivity of 18F-DOPA PET in the detection of paraganglioma and its metastatic lesions and to evaluate whether tracer uptake by the tumors is enhanced by carbidopa. Methods: Two patients with nonmetastatic adrenal pheochromocytoma, and 9 patients with extraadrenal abdominal paraganglioma (1 nonmetastatic, 8 metastatic), underwent whole-body CT, MRI, baseline 18F-DOPA PET, and 18F-DOPA PET with oral preadministration of 200 mg of carbidopa. The dynamics of tracer uptake by these lesions and the physiologic distribution of 18F-DOPA in normal tissues were recorded. Results: Seventy-eight lesions were detected by CT or MRI, 54 by baseline 18F-DOPA PET (P = 0.0022 vs. CT/MRI), and 57 by 18F-DOPA PET plus carbidopa (P = 0.0075 vs. CT/MRI, not statistically significant vs. baseline). In reference to findings on CT and MRI, the sensitivities of baseline 18F-DOPA PET were 47.4% for lesions and 55.6% for positive body regions, versus 50.0% (lesions) and 66.7% (regions) for 18F-DOPA PET plus carbidopa (neither is statistically significant vs. baseline). Compared with baseline, carbidopa detected additional lesions in 3 (27%) of 11 patients. Carbidopa increased the mean (±SD) peak standardized uptake value in index tumor lesions from 6.4 ± 3.9 to 9.1 ± 5.6 (P = 0.037). Pancreatic physiologic 18F-DOPA uptake, which may mask adrenal pheochromocytoma, is blocked by carbidopa. Conclusion: Carbidopa enhances the sensitivity of 18F-DOPA PET for adrenal pheochromocytomas and extraadrenal abdominal paragangliomas by increasing the tumor-to-background ratio of tracer uptake. The sensitivity of 18F-DOPA PET for metastases of paraganglioma appears to be limited.