Karen T. Adams

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.

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.

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.

Comparison of 6-18F-Fluorodopamine PET with 123I-Metaiodobenzylguanidine and 111In-Pentetreotide Scintigraphy in Localization of Nonmetastatic and Metastatic Pheochromocytoma

We compared functional imaging modalities including PET with 6-18F-fluorodopamine (18F-DA) with 123I-metaiodobenzylguanidine (123I-MIBG) and somatostatin receptor scintigraphy (SRS) with 111In-pentetreotide in nonmetastatic and metastatic pheochromocytoma (PHEO). Methods: We studied 25 men and 28 women (mean age ± SD, 44.2 ± 14.2 y) with biochemically proven nonmetastatic (n = 17) or metastatic (n = 36) PHEO. Evaluation included anatomic imaging with CT or MRI and functional imaging that included at least 2 nuclear medicine modalities: 18F-DA PET, 123I-MIBG scintigraphy, or SRS. Sensitivity of functional imaging versus anatomic imaging was assessed on a per-patient and a per-region basis. Results: For this available cohort, on a per-patient basis overall sensitivity (combined for nonmetastatic and metastatic PHEO) was 90.2% for 18F-DA PET, 76.0% for 123I-MIBG scintigraphy, and 22.0% for SRS. On a per-region basis, overall sensitivity was 75.4% for 18F-DA PET, 63.4% for 123I-MIBG scintigraphy, and 64.0% for SRS. Conclusion: If available, 18F-DA PET should be used in the evaluation of PHEO, because it is more sensitive than 123I-MIBG scintigraphy or SRS. If 18F-DA PET is not available, 123I-MIBG scintigraphy (for nonmetastatic or adrenal PHEO) and SRS (for metastatic PHEO) should be the first alternative imaging methods to be used.

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.

Functional Imaging of SDHx-Related Head and Neck Paragangliomas: Comparison of 18F-Fluorodihydroxyphenylalanine, 18F-Fluorodopamine, 18F-Fluoro-2-Deoxy-d-Glucose PET, 123I-Metaiodobenzylguanidine Scintigraphy, and 111In-Pentetreotide Scintigraphy

RATIONALE Accurate diagnosis of head and neck paragangliomas is often complicated by biochemical silence and lack of catecholamine-associated symptoms, making accurate anatomical and functional imaging techniques essential to the diagnostic process. METHODS Ten patients (seven SDHD, three SDHB), with a total of 26 head and neck paragangliomas, were evaluated with anatomical and functional imaging. This study compares five different functional imaging techniques [(18)F-fluorodihydroxyphenylalanine ((18)F-FDOPA) positron emission tomography (PET), (18)F-fluorodopamine ((18)F-FDA) PET/computed tomography (CT), (18)F-fluoro-2-deoxy-D-glucose ((18)F-FDG) PET/CT, (123)I-metaiodobenzylguanidine ((123)I-MIBG) scintigraphy, and (111)In-pentetreotide scintigraphy] in the localization of head and neck paragangliomas. RESULTS Prospectively (18)F-FDOPA PET localized 26 of 26 lesions in the 10 patients, CT/magnetic resonance imaging localized 21 of 26 lesions, (18)F-FDG PET/CT localized 20 of 26 lesions, (111)In-pentetreotide scintigraphy localized 16 of 25 lesions, (18)F-FDA PET/CT localized 12 of 26 lesions, and (123)I-MIBG scintigraphy localized eight of 26 lesions. Differences in imaging efficacy related to genetic phenotype, even in the present small sample size, included the negativity of (18)F-FDA PET/CT and (123)I-MIBG scintigraphy in patients with SDHB mutations and the accuracy of (18)F-FDG PET/CT in all patients with SDHD mutations, as compared with the accuracy of (18)F-FDG PET/CT in only one patient with an SDHB mutation. CONCLUSION Overall, (18)F-FDOPA PET proved to be the most efficacious functional imaging modality in the localization of SDHx-related head and neck paragangliomas and may be a potential first-line functional imaging agent for the localization of these tumors.

Superiority of [68Ga]-DOTATATE PET/CT to other functional imaging modalities in the localization of SDHB-associated metastatic pheochromocytoma and paraganglioma

Purpose: Patients with succinate dehydrogenase subunit B(SDHB) mutation–related pheochromocytoma/paraganglioma (PHEO/PGL) are at a higher risk for metastatic disease than other hereditary PHEOs/PGLs. Current therapeutic approaches are limited, but the best outcomes are based on the early and proper detection of as many lesions as possible. Because PHEOs/PGLs overexpress somatostatin receptor 2 (SSTR2), the goal of our study was to assess the clinical utility of [68Ga]-DOTA(0)-Tyr(3)-octreotate ([68Ga]-DOTATATE) positron emission tomography/computed tomography (PET/CT) and to evaluate its diagnostic utility in comparison with the currently recommended functional imaging modalities [18F]-fluorodopamine ([18F]-FDA), [18F]-fluorodihydroxyphenylalanine ([18F]-FDOPA), [18F]-fluoro-2-deoxy-d-glucose ([18F]- FDG) PET/CT as well as CT/MRI. Experimental Design: [68Ga]-DOTATATE PET/CT was prospectively performed in 17 patients with SDHB-related metastatic PHEOs/PGLs. All patients also underwent [18F]-FDG PET/CT and CT/MRI, with 16 of the 17 patients also receiving [18F]-FDOPA and [18F]-FDA PET/CT scans. Detection rates of metastatic lesions were compared between all these functional imaging studies. A composite synthesis of all used functional and anatomical imaging studies served as the imaging comparator. Results: [68Ga]-DOTATATE PET/CT demonstrated a lesion-based detection rate of 98.6% [95% confidence interval (CI), 96.5%–99.5%], [18F]-FDG, [18F]-FDOPA, [18F]-FDA PET/CT, and CT/MRI showed detection rates of 85.8% (CI, 81.3%–89.4%; P < 0.01), 61.4% (CI, 55.6%–66.9%; P < 0.01), 51.9% (CI, 46.1%–57.7%; P < 0.01), and 84.8% (CI, 80.0%–88.5%; P < 0.01), respectively. Conclusions: [68Ga]-DOTATATE PET/CT showed a significantly superior detection rate to all other functional and anatomical imaging modalities and may represent the preferred future imaging modality in the evaluation of SDHB-related metastatic PHEO/PGL. Clin Cancer Res; 21(17); 3888–95. ©2015 AACR. See related commentary by Hofman and Hicks, p. 3815

Biochemical diagnosis, localization and management of pheochromocytoma: focus on multiple endocrine neoplasia type 2 in relation to other hereditary syndromes and sporadic forms of the tumour

Approximately 50% of patients with multiple endocrine neoplasia (MEN) 2A or 2B develop pheochromocytoma. These tumours are almost exclusively benign and localized in the adrenal glands. About one‐third are bilateral at initial diagnosis. Amongst patients with pheochromocytoma, those with MEN 2A have subtler symptoms compared to those with sporadic disease. Since pheochromocytomas in patients with MEN 2 often secrete catecholamines episodically (but metabolize them continuously to metanephrines), the first choice for biochemical diagnosis is the measurement of free metanephrines in plasma, with urinary fractionated metanephrines being the second choice. In patients with pheochromocytomas that produce exclusively normetanephrine, MEN 2 can be excluded. In patients with biochemically proven MEN 2‐related pheochromocytoma, anatomical imaging of the adrenals (with either computerized tomography or magnetic resonance) should be obtained next. Functional imaging with specific ligands (e.g. scintigraphy with [123I]‐metaiodobenzylguanidine or, if available, positron emission tomography with [18F]‐fluorodopamine, [18F]‐dihydroxyphenylalanine, [11C]‐adrenaline or [11C]‐hydroxyephedrine) may then be particularly useful in patients with distorted anatomy from previous surgery, in cases of equivocal biochemical data despite high clinical suspicion for a tumour, to rule out multifocal disease, or where there is suspicion of metastatic disease (e.g. tumours larger than 5 cm). Laparoscopic surgery is the treatment of choice and subtotal (cortical‐sparing) adrenalectomy is the procedure of choice in bilateral pheochromocytomas.