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The role of 6-[18F]fluorodopamine positron emission tomography in the localization of adrenal pheochromocytoma associated with von Hippel–Lindau syndrome
Abstract
[(123/131)I]metaiodobenzylguanidine (MIBG) scintigraphy is considered as the gold standard in the localization of pheochromocytoma. However, this method has less optimal sensitivity for the detection of pheochromocytoma associated with von Hippel-Lindau (VHL). Our preliminary results suggest that this is partially due to the low expression of cell membrane norepinephrine transporter system in VHL-related pheochromocytoma cells. Another probable cause may be the low affinity that [(123/131)I]MIBG has for these cells. Recently, 6-[(18)F]fluorodopamine ([(18)F]DA) positron emission tomography (PET) has been introduced as a novel functional imaging modality with high sensitivity for pheochromocytoma. Therefore, we investigated whether [(18)F]DA PET is more effective than [(123/131)I]MIBG scintigraphy in the diagnostic localization of VHL-related adrenal pheochromocytoma.
In this study, we evaluated seven VHL patients in whom adrenal pheochromocytomas were confirmed by histopathology results. Adrenal pheochromocytomas were localized using computed tomography (CT), magnetic resonance imaging (MRI), [(123/131)I]MIBG scintigraphy and [(18)F]DA PET.
[(18)F]DA PET localized pheochromocytoma in all the seven patients, as did in CT. In contrast, three out of the seven had negative results utilizing [(123/131)I]MIBG scintigraphy and one out of the six patients had negative MRI results.
[(18)F]DA PET was found to show more promising results when compared with [(123/131)I]MIBG scintigraphy in the diagnostic localization of VHL-related adrenal pheochromocytoma, with a 100% rate of localization. Thus, [(18)F]DA PET in conjunction with CT/MRI should be considered as an effective method for the proper localization of VHL-related adrenal pheochromocytoma.
... The sensitivity appears to be lower for extraadrenal, metastatic, recurrent, and certain hereditary PPGLs (14,16,(21)(22)(23)(24). Metastatic lesions might be missed because of cell dedifferentiation and, consequently, loss of NET or VMAT expression. It has been demonstrated that sensitivity was especially low in SDHB-and VHL-related PPGLs (22,25,26). Theoretically, the amount of uptake and, consequently, tumor visualization and susceptibility for 131 I-MIBG therapy might be dependent of the underlying genotype. ...
... Similar to 123 I-MIBG, several PET tracers specifically target catecholamine synthesis, storage, and secretion pathways including 18 F-fluorodihydroxyphenylalanine and 18 F-fluorodopamine. Kaji et al. showed that 18 F-fluorodihydroxyphenylalanine PET is superior to 123 I-MIBG scintigraphy in the context of von Hippel-Lindau syndrome (26). We have previously shown that 18 F-FDG PET can distinguish between PPGLs with different underlying genotypes, and sensitivity of 18 F-FDG PET is higher in SDHB/Drelated PPGLs than non-SDHB/D-related metastatic PPGLs (92% vs. 37%) (38). ...
... We have previously shown that 18 F-FDG PET can distinguish between PPGLs with different underlying genotypes, and sensitivity of 18 F-FDG PET is higher in SDHB/Drelated PPGLs than non-SDHB/D-related metastatic PPGLs (92% vs. 37%) (38). The sensitivity of 123 I-MIBG scintigraphy appears to be lower in VHL-and SDHB-related PPGLs (22,25,26). On the basis of these studies and the differences in catecholamine transporter expression between genotypes, we hypothesized that a genotype-dependent imaging phenotype also exists for 123 I-MIBG scintigraphy. ...
(123)I-metaiodobenzylguanidine ((123)I-MIBG) scintigraphy plays an important role in the diagnostic evaluation of patients with pheochromocytoma and paraganglioma (PPGL). MIBG targets cell membrane and vesicular catecholamine transporters of chromaffin cells and facilitates localization of the primary tumor and metastatic lesions. Its specificity for the diagnosis of adrenomedullary chromaffin cell tumors can be jeopardized by physiological uptake by the normal adrenal medulla. The aim of this study was to distinguish between PPGLs and normal adrenal glands by evaluating semi-quantitative (123)I-MIBG uptake and to examine genotype-specific differences in correlation with expression of catecholamine transporter systems.
Sixty-two PPGLs collected from 57 patients with hereditary mutations in SDHA (n = 1), SDHB (n = 2), SDHD (n = 4), VHL (n = 2), RET (n = 12), NF1 (n = 2), MAX (n = 1) and with sporadic PPGLs (n = 33) were investigated. Pre-operative planar and single-photon emission computed tomographic (SPECT) images were semi-quantitatively analyzed using uptake measurements. Tumor-to-liver (T/L) and normal-adrenal-to-liver (NA/L) ratios were calculated and correlated with clinical characteristics including genotype, tumor size and plasma metanephrines concentrations. The expression of norepinephrine transporter (NET) and vesicular monoamine transporter (VMAT-1) was evaluated immunohistochemically in paraffin-embedded tumor tissues.
Mean T/L ratios of PPGL lesions were significantly higher than NA/L ratios (p<0.001). Cut-off values to distinguish between physiological and pathological adrenal uptake were established at 0.7 (100% sensitivity, 10.3% specificity) and 4.3 (100% specificity, 66.1% sensitivity). No statistically significant differences in (123)I-MIBG uptake were found across PPGLs of different genotypes. Mean NET expression in hereditary cluster 2 (RET, NF1, MAX) and apparently sporadic tumors was significantly higher than for hereditary cluster 1 (SDHx, VHL) PPGLs (P = 0.011 and P = 0.006, respectively). Mean VMAT-1 expression in hereditary cluster 1 PPGLs was significantly higher than for cluster 2 tumors (P = 0.010). (123)I-MIBG uptake significantly correlated with maximum tumor diameter (P = 0.002). MIBG uptake, however, did not correlate with either NET or VMAT-1 expression.
Liver normalized semi-quantitative (123)I-MIBG uptake may be helpful to distinguish between pheochromocytoma and physiological adrenal uptake. Genotype-specific differences in expression of NET and VMAT-1 do not translate into differences in (123)I-MIBG uptake.
Copyright © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
... After PPGL is biochemically proven, anatomical imaging with computed tomography (CT) or magnetic resonance imaging (MRI) is performed. Upon CT or MRI lesion confirmation, the patient's biochemical phenotype and tumor size, as well as metastatic potential, plays a determining role in whether further imaging with functional studies is required (53,54). PPGL patients with a single, epinephrine or metanephrine secreting adrenal mass less than 5 cm, will most likely not benefit from functional imaging, since these tumors are confined to the adrenal gland and present with a small likelihood of metastases (53). ...
... PPGL patients with a single, epinephrine or metanephrine secreting adrenal mass less than 5 cm, will most likely not benefit from functional imaging, since these tumors are confined to the adrenal gland and present with a small likelihood of metastases (53). However, for lesions greater than 5 cm, secreting norepinephrine or normetanephrine, located extra-adrenally, or associated with a hereditary tumor syndrome such as SDHB, the metastatic potential is much higher and functional imaging is necessary to determine the extent of disease (53,54). ...
Objective:
Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors derived from adrenal or extra-adrenal locations, respectively. Upon suspicion of PPGL, specific metabolomic, molecular, biochemical, imaging, and histopathologic studies are performed to prove, localize, treat, and monitor disease progression. Improved diagnostic tools allow physicians to accurately diagnose PPGL, even in patients presenting with small (<1 cm) or biochemically silent tumors, which previously delayed proper detection and treatment.
Methods:
This review outlines the most updated approach to PPGL patients and presents a new diagnostic protocol for physicians to increase earlier tumor identification and accurately assess metastatic behavior.
Conclusion:
We present the most recent advances in genetics, epigenetics, metabolomics, biochemical, and imaging diagnoses of this rare tumor to properly assess disease, decide treatment options, and manage follow-up. We also elaborate on new therapeutic perspectives in these very rare neoplastic entities.
Abbreviations:
ATRX = ATRX chromatin remodeler; ccRCC = clear cell renal cell carcinoma; c-MYC = MYC proto oncognene; CT = computed tomography; DOTATATE = DOTA-octreotate; EGLN1/2 = egl-9 family hypoxia inducible factor 1/2; EGLN2/PHD1 = egl-9 family hypoxia inducible factor 2; EPAS1/HIF2A = endothelial PAS domain protein 2/hypoxia-inducible factor 2α; ERK = extracellular signal-regulated kinase; HIFs = hypoxia-inducible factors; HIF-α = hypoxia-inducible factor alpha; HNPGLs = head and neck paragangliomas; 177Lu-DOTATATE = lutetium octreotate; MAX = myc-associated factor X; MDH2 = malate dehydrogenase; MIBG = metaiodobenzylguanidine; MN = metanephrine; MRI = magnetic resonance imaging; mTOR = mammalian target of rapamycin; NETs = neuroendocrine tumors; NF1 = neurofibromin 1; NMN = normetanephrine; PHD = prolyl hydroxylase domain protein; PI3K = phosphoinositide 3-kinase; PPGLs = pheochromocytoma and paragangliomas; PRRT = peptide receptor radionuclide therapy; Pvhl = von Hippel-Lindau protein; RAS = rat sarcoma oncogene; RET = rearranged during transfection proto-oncogene; SDH = succinate dehydrogenase; SDHA, -B, -C, -D = succinate dehydrogenase subunits A, B, C, D; SDHAF2 = succinate dehydrogenase complex assembly factor 2; SDHB, C, D = succinate dehydrogenase subunits B, C, D; SDHx = succinate dehydrogenase subunits; SSTRs = somatostatin receptors; VHL = von Hippel-Lindau.
... Как и 123 / 131 I-МЙБГ, 18 F-FDA нацелен на транспортер норэпинефрина, имея достаточно высокую чувствительность для первичных ПГ (77-100%) и их метастазов (77-90%) [79][80][81] и специфичность около 90% [80]. 18 F-FDA продемонстрировал свою большую аффинность к транспортеру норэпинефрина, что делает его более эффективным в визуализации ПГ в составе VHLсиндрома по сравнению с 123 I-МЙБГ ввиду сниженной продукции транспортера в опухолях с VHL-мутацией [82]. В случае первичных ФХ эффективность 18 F-FDA ПЭТ сопоставима с ПЭТ с 18 F-DOPA и 123 I-МЙБГ сцинтиграфией [83]. ...
Th e diagnosis of adrenal tumors has improved signifi cantly over the past decades thanks to laboratory research and anatomical imaging techniques. In some cases, these methods make it possible to distinguish a benign tumor from a malignant one, and in combination with invasive methods, the accuracy of such diagnostics varies from 80 to 100%. However, in cases of pheochromocytoma, this invasive intervention can induce a hypertensive crisis. Hybrid molecular imaging techniques such as single-photon emission tomography (SPECT) and positron emission tomography (PET), coupled with CT or MRI, have come to the rescue. Molecular imaging techniques are non-invasive and safe for patients, and the information obtained allows you to more accurately determine the optimal treatment tactics. Purpose: in our review, we will try to cover all modern and promising methods of molecular imaging of adrenal formations and radionuclide therapy, which constitute a new trend in the development of nuclear medicine in the world - radiotheranostics (radionuclide therapy based on radionuclide diagnostics). Methods: We conducted a systematic review of the literature obtained from the open databases Scopus and Pubmed describing the latest methods of radiotherapy of adrenal tumors. We then classifi ed the findings based on mechanism of action, point of application, and relevance of radioactive tracers, comparing their effectiveness and availability.
... Как и 123 / 131 I-МЙБГ, 18 F-FDA нацелен на транспортер норэпинефрина, имея достаточно высокую чувствительность для первичных ПГ (77-100%) и их метастазов (77-90%) [79][80][81] и специфичность около 90% [80]. 18 F-FDA продемонстрировал свою большую аф--FDA продемонстрировал свою большую аф-FDA продемонстрировал свою большую аф-продемонстрировал свою большую аффинность к транспортеру норэпинефрина, что делает его более эффективным в визуализации ПГ в составе VHLсиндрома по сравнению с 123 I-МЙБГ ввиду сниженной продукции транспортера в опухолях с VHL-мутацией [82]. В случае первичных ФХ эффективность 18 F-FDA ПЭТ сопоставима с ПЭТ с 18 F-DOPA и 123 I-МЙБГ сцин--МЙБГ сцинтиграфией [83]. ...
The diagnosis of adrenal tumors has improved significantly over the past decades thanks to laboratory research and anatomical imaging techniques. In some cases, these methods make it possible to distinguish a benign tumor from a malignant one, and in combination with invasive methods, the accuracy of such diagnostics varies from 80 to 100%. However, in cases of pheochromocytoma, this invasive intervention can induce a hypertensive crisis. Hybrid molecular imaging techniques such as single-photon emission tomography (SPECT) and positron emission tomography (PET), coupled with CT or MRI, have come to the rescue. Molecular imaging techniques are non-invasive and safe for patients, and the information obtained allows you to more accurately determine the optimal treatment tactics. Purpose: in our review, we will try to cover all modern and
promising methods of molecular imaging of adrenal formations and radionuclide therapy, which constitute a new trend in the development of nuclear medicine in the world - radiotheranostics (radionuclide therapy based on radionuclide diagnostics).
Methods: We conducted a systematic review of the literature obtained from the open databases Scopus and Pubmed describing the latest methods of radiotherapy of adrenal tumors. We then classified the findings based on mechanism of action, point of
application, and relevance of radioactive tracers, comparing their effectiveness and availability
... 123 I-MIBG scan is mandatory for candidate patients for 131 I-MIBG therapy [13]. It has to be noted, however, that in contrast to 68 Ga-DOTATATE-PET and 18 F-FDG-PET, MIBG scintigraphy yields lower sensitivity for the diagnosis of VHL and SDHx mutation-related PPGL and metastatic lesions [13,[109][110][111] and prediction of MIBG uptake based on the genetic background of PPGL alone is difficult [112]. ...
Pheochromocytomas and paragangliomas are the most heritable endocrine tumors. In addition to the inherited mutation other driver mutations have also been identified in tumor tissues. All these genetic alterations are clustered in distinct groups which determine the pathomechanisms. Most of these tumors are benign and their surgical removal will resolve patient management. However, 5–15% of them are malignant and therapeutical possibilities for them are limited. This review provides a brief insight about the tumorigenesis associated with pheochromocytomas/paragangliomas in order to present them as potential therapeutical targets.
... Similar to MIBG, due to its ability to be taken up by NET, 18 F-6F-dopamine is also used for diagnostic localization of PCC with high sensitivity (Pacak et al. 2001), with superior outcome compared to 123 I-MIBG (Ilias et al. 2003;Mamede et al. 2006;Kaji et al. 2007). In several patient studies, 18 F-6F-dopamine showed equal sensitivity to localize nonmetastatic PCC when compared to 123 I-MIBG, but much better for metastatic ones (Ilias et al. 2008;Timmers et al. 2009a, b). ...
The norepinephrine transporter (NET) is a major target for the evaluation of the cardiac sympathetic nerve system in patients with heart failure and Parkinson's disease. It is also used in the therapeutic applications against certain types of neuroendocrine tumors, as exemplified by the clinically used 123/131I-MIBG as theranostic single-photon emission computed tomography (SPECT) agent. With the development of more advanced positron emission tomography (PET) technology, more radiotracers targeting NET have been reported, with superior temporal and spatial resolutions, along with the possibility of functional and kinetic analysis. More recently, fluorine-18-labelled NET tracers have drawn increasing attentions from researchers, due to their longer radiological half-life relative to carbon-11 (110 min vs. 20 min), reduced dependence on on-site cyclotrons, and flexibility in the design of novel tracer structures. In the heart, certain NET tracers provide integral diagnostic information on sympathetic innervation and the nerve status. In the central nervous system, such radiotracers can reveal NET distribution and density in pathological conditions. Most radiotracers targeting cardiac NET-function for the cardiac application consistent of derivatives of either norepinephrine or MIBG with its benzylguanidine core structure, e.g. 11C-HED and 18F-LMI1195. In contrast, all NET tracers used in central nervous system applications are derived from clinically used antidepressants. Lastly, possible applications of NET as selective tracers over organic cation transporters (OCTs) in the kidneys and other organs controlled by sympathetic nervous system will also be discussed.
... Subsequently, larger studies including large numbers of extra-adrenal, multiple, recurrent, and hereditary PGLs found sensitivity of 52-75% [51,[53][54][55]. It is currently well known and repeatedly documented that [ 123 I]MIBG scintigraphy should not be used for patients with SDHB-associated PPGLs, less than 50% of which exhibit positivity [52,57,58]. This is also true for metastatic PPGLs [51,55,[59][60][61][62]. ...
Purpose
Diverse radionuclide imaging techniques are available for the diagnosis, staging, and follow-up of phaeochromocytoma and paraganglioma (PPGL). Beyond their ability to detect and localise the disease, these imaging approaches variably characterise these tumours at the cellular and molecular levels and can guide therapy. Here we present updated guidelines jointly approved by the EANM and SNMMI for assisting nuclear medicine practitioners in not only the selection and performance of currently available single-photon emission computed tomography and positron emission tomography procedures, but also the interpretation and reporting of the results.
Methods
Guidelines from related fields and relevant literature have been considered in consultation with leading experts involved in the management of PPGL. The provided information should be applied according to local laws and regulations as well as the availability of various radiopharmaceuticals.
Conclusion
Since the European Association of Nuclear Medicine 2012 guidelines, the excellent results obtained with gallium-68 (⁶⁸Ga)-labelled somatostatin analogues (SSAs) in recent years have simplified the imaging approach for PPGL patients that can also be used for selecting patients for peptide receptor radionuclide therapy as a potential alternative or complement to the traditional theranostic approach with iodine-123 (¹²³I)/iodine-131 (¹³¹I)-labelled meta-iodobenzylguanidine. Genomic characterisation of subgroups with differing risk of lesion development and subsequent metastatic spread is refining the use of molecular imaging in the personalised approach to hereditary PPGL patients for detection, staging, and follow-up surveillance.
... However, a vast majority of patients who require imaging work-up and hormonal testing to exclude PCC/PGL have so-called "adrenal incidentalomas," found on imaging that was performed ( 18 F-DOPA) [14][15][16][17][18][19], 18 F-Dopamine ( 18 F-DA) [20][21][22][23], 68 Ga-DOTA-somatostatin analogs [15,[24][25][26][27] and 11 C-hydroxy ephedrine ( 11 C-HED) [28][29][30][31][32] for PET/CT. 11 C-HED is a norepinephrine analog that binds to the norepinephrine transporter and has previously shown high diagnostic sensitivity and specificity in patients with PCC/PGL [28], including post-operative surveillance following PCC/PGL resection [29] as well as for other tumors such as neuroblastoma [33,34]. ...
Pheochromocytomas (PCC) and paragangliomas (PGL) may be difficult to diagnose because of vague and uncharacteristic symptoms and equivocal biochemical and radiological findings. This was a retrospective cohort study in 102 patients undergoing 11C-hydroxy-ephedrine (11C-HED)-PET/CT because of symptoms and/or biochemistry suspicious for PCC/PGL and/or with radiologically equivocal adrenal incidentalomas. Correlations utilized CT/MRI, clinical, biochemical, surgical, histopathological and follow-up data. 11C-HED-PET/CT correctly identified 19 patients with PCC and six with PGL, missed one PCC, attained one false positive result (nodular hyperplasia) and correctly excluded PCC/PGL in 75 patients. Sensitivity, specificity, positive and negative predictive values of 11C-HED-PET/CT for PCC/PGL diagnosis was 96%, 99%, 96% and 99%, respectively. In 41 patients who underwent surgical resection and for whom correlation to histopathology was available, the corresponding figures were 96%, 93%, 96% and 93%, respectively. Tumor 11C-HED-uptake measurements (standardized uptake value, tumor-to-normal-adrenal ratio) were unrelated to symptoms of catecholamine excess (p > 0.05) and to systolic blood pressure (p > 0.05). In PCC/PGL patients, norepinephrine and systolic blood pressure increased in parallel (R2 = 0.22, p = 0.016). 11C-HED-PET/CT was found to be an accurate tool to diagnose and rule out PCC/PGL in complex clinical scenarios and for the characterization of equivocal adrenal incidentalomas. PET measurements of tumor 11C-HED uptake were not helpful for tumor characterization.
... However, not all forms of PPC/PPG concentrate mIBG. In case of malignant transformation or tumor dedifferentiation, in succinate dehydrogenase subunit B mutation (SDHB), von Hippel-Lindau syndrome, and in patients with dopamine-secreting forms, PPCs and PPGs can be mIBG-negative [64][65][66], hence the need for a baseline pre-radionuclide therapy assessment. ...
Neuroblastoma (NB), the most common extracranial tumor of pediatric age, arises in the adrenal medulla or paraspinal sympathetic ganglia, and presents as neck, chest, or abdomen mass; around 50% of NB are metastatic at diagnosis. Catecholamine and metanephrine levels are increased in 90% of patients and are used for the biochemical diagnosis. ¹²³I-meta-iodobenzylguanidine (MIBG) scintigraphy is a fundamental diagnostic technique for the diagnosis, staging, and restaging of NB. The therapeutic approach for high-risk NB includes induction chemotherapy, followed by surgery and subsequent myeloablative chemotherapy associated to autologous hematopoietic stem cell transplantation. ¹³¹I-MIBG therapy is mostly indicated in high-risk NB patients with evidence of persistence of MIBG-avid metastatic disease, and has an overall response of 30%. ¹³¹I-MIBG therapy is generally safe but acute toxicity (nausea, anorexia, and vomiting) can occur. Hematological toxicity (anemia, leukocytopenia, and mostly thrombocytopenia) usually appears 2–4 weeks after infusion, the recovery can be very slow, and sometimes requires stem cell support. Long-term secondary malignancies are rare.
... For example, VHLrelated PPGL cells express the cell membrane norepinephrine transporter system at lower rates than MEN2-related tumor cells [30]. Since MIBG has low affinity for these cells than 18 F-fluorodopamine, it is no surprise that 18 F-FDA PET is more sensitive than 123 I-MIBG scintigraphy in patients with VHL-related pheochromacytomas [31]. 18 F-FDG PET CT has a perfect sensitivity for SDHB positive metastatic PPGLs while 123 I-MIBG scintigraphy has much lower performance(about 50% or less) [32]. ...
... 18 F-fluorodihydroxyphenylalanine ( 18 F-fluorodopa, 18 F-FDOPA) is taken up through neutral amino acid transporters (mainly LAT1/LAT2), decarboxylated into 18 F-fluorodopamine by aromatic L-amino acid decarboxylase, and concentrated in intracellular vesicles. 18 F-FDOPA PET/CT was found to be a highly sensitive (>90%) and specific (95-100%) imaging modality for PHEO detection (Fiebrich et al. 2009;Fonte et al. 2012;Hoegerle et al. 2002;Ilias et al. 2008;Kaji et al. 2007;Timmers et al. 2009a, b). A special advantage of 18 F-FDOPA over other specific radiopharmaceuticals is the lack of uptake by the healthy adrenal tissue. ...
Pheochromocytomas and their extra-adrenal counterpart paragangliomas (PGLs; together called PPGLs), belong to the family of neural crest-derived tumors. Given the overexpression of a wide variety of specific targets in PPGLs, it seems that these tumors are optimally suited to be imaged by specific radiopharmaceuticals. Thus, theranostics approaches with somatostatin agonists and antagonists are rapidly evolving in the setting of these tumors and may be considered as the next step in the therapeutic arsenal of metastatic PPGLs.
... Interestingly, in a study of 34 PHEO patients (of whom n = 3 reported with VHL), 18 F-DOPA PET/CT had equivocal results for adrenal uptake (36). 18 F-FDA PET was superior to 123 I-MIBG in the context of VHL syndrome: in 7/7 VHL patients, all their PHEOs were imaged (two patients had bilateral disease) with the former modality, whereas the latter was positive in 4/7 patients (37). ...
p>Few reports have presented data and results on functional (i.e., nuclear medicine) imaging of paragangliomas and pheochromocytomas (PGLs/PHEOs) for von Hippel–Lindau (VHL) patients. Nuclear medicine localization modalities for chromaffin tumors can be specific or nonspecific. Specific methods make use of the expression of the human norepinephrine transporter (hNET) and vesicular monoamine transporters (VMATs) by these tumors. These permit the use of radiolabeled ligands that enter the synthesis and storage pathway of catecholamines. Nonspecific methods are not related to the synthesis, uptake, or storage of catecholamines but make use of the tumors’ high glucose metabolism or expression of somatostatin receptors. Consensuses and guidelines suggest that metastatic and sporadic PHEOs/PGLs in VHL patients (as in patients with chromaffin tumors of yet unknown genotype) should be evaluated first with <sup>18</sup>F-dihydroxyphenylalanine (<sup>18</sup>F-DOPA) positron emission tomography/computed tomography (PET/CT). The functional imaging of second choice is <sup>123</sup>I-metaiodobenzylguanidine (<sup>123</sup>I-MIBG) for PHEOs in VHL patients. <sup>123</sup>I-MIBG, <sup>68</sup>Ga-DOTATATE/DOTATOC/DOTANOC PET/CT, or <sup>18</sup>F-fluorodeoxyglucose (<sup>18</sup>F-FDG) PET/CT can be a second choice of functional imaging for PGLs in VHL patients.</p
... Additionally, lower sensitivity is reported in those with familial PGL and extraadrenal disease (39,40). False-negative scans are more frequent in those with the SDHB mutation or von Hippel-Lindau syndrome-associated PHEO (41), probably due to lower expression of NET. In a prospective study in 140 patients, 123 I-MIBG showed specificity of 82% and sensitivity of 88% for PHEO and 67% for PGL (42). ...
The norepinephrine transporter (NET) is essential for norepinephrine uptake at the synaptic terminals and adrenal chromaffin cells. In neuroendocrine tumors, NET can be targeted for imaging as well as therapy. One of the most widely used theranostic agents targeting NET is metaiodobenzylguanidine (MIBG), a guanethidine analog of norepinephrine. ¹²³I/¹³¹I-MIBG theranostics have been applied in the clinical evaluation and management of neuroendocrine tumors, especially in neuroblastoma, paraganglioma, and pheochromocytoma. ¹²³I-MIBG imaging is a mainstay in the evaluation of neuroblastoma, and ¹³¹I-MIBG has been used for the treatment of relapsed high-risk neuroblastoma for several years, however, the outcome remains suboptimal. ¹³¹I-MIBG has essentially been only palliative in paraganglioma/pheochromocytoma patients. Various techniques of improving therapeutic outcomes, such as dosimetric estimations, high-dose therapies, multiple fractionated administration and combination therapy with radiation sensitizers, chemotherapy, and other radionuclide therapies, are being evaluated. PET tracers targeting NET appear promising and may be more convenient options for the imaging and assessment after treatment. Here, we present an overview of NET as a target for theranostics; review its current role in some neuroendocrine tumors, such as neuroblastoma, paraganglioma/ pheochromocytoma, and carcinoids; and discuss approaches to improving targeting and theranostic outcomes. COPYRIGHT © 2017 by the Society of Nuclear Medicine and Molecular Imaging.
... This may be due to reduced expression of norepinephrine transporters in malignant adrenal tumors or dedifferentiation. It has been shown that tumors associated with VHL and SDHB genetic mutations may express a reduced number of noradrenaline transporters and, therefore, are more likely to be negative on MIBG imaging [46,47]. ...
... 6-[ 18 F]F-DA is also taken up selectively in neuroendocrine tumors, which accumulate and store catecholamine derivatives recognized by the cell membrane norepinephrine transporter (NET). 14,15 Pacek and coworkers demonstrated that 6-[ 18 F]F-DA is more sensitive and effective at localizing pheochromocytomas and paragangliomas than either meta-[ 131 I]iodobenzyl guanidine ([ 131 I]MIBG) or [ 123 I]MIBG, the clinically used NET-mediated radiopharmaceuticals. [16][17][18][19][20][21] Given these observations and the inherent advantages of 18 F compared to 123 I/ 124 I/ 131 Iradionuclides (decay purity, tissue penetration range, half-life), 6-[ 18 F]F-DA may prove to be superior compared to MIBG for imaging neuroendocrine tumors and micrometastases. Neuroblastoma (NB) is a neuroendocrine tumor of neural crest origin, and, as such, possesses sympathetic neuronal behavior. ...
6-[(18) F]Fluorodopamine (6-[(18) F]F-DA) is a positron emission tomography radiopharmaceutical used to image sympathetic cardiac innervation and neuroendocrine tumors. Imaging with 6-[(18) F]F-DA is constrained, in part, by the bioactivity and neurotoxicity of 6-[(19) F]fluorodopamine. Furthermore, routine access to this radiotracer is limited by the inherent difficulty of incorporation of [(18) F]fluoride into electron-rich aromatic substrates. We describe the simple and direct preparation of high specific activity (SA) 6-[(18) F]F-DA from no-carrier-added (n.c.a.) [(18) F]fluoride. Incorporation of n.c.a. [(18) F]fluoride into a diaryliodonium salt precursor was achieved in 50-75% radiochemical yields (decay corrected to end of bombardment). Synthesis of 6-[(18) F]F-DA on the IBA Synthera® and GE TRACERlab FX-FN automated platforms gave 6-[(18) F]F-DA in >99% chemical and radiochemical purities after HPLC purification. The final non-corrected yields of 6-[(18) F]F-DA were 25 ± 4% (n = 4, 65 min) and 31 ± 6% (n = 3, 75 min) using the Synthera and TRACERlab modules, respectively. Efficient access to high SA 6-[(18) F]F-DA from a diaryliodonium salt precursor and n.c.a. [(18) F]fluoride is provided by a relatively subtle change in reaction conditions - replacement of a polar aprotic solvent (acetonitrile) with a relatively nonpolar solvent (toluene) during the critical radiofluorination reaction. Implementation of this process on common radiochemistry platforms should make 6-[(18) F]F-DA readily available to the wider imaging community.
... 18 F-fl uorodopamine (FDA) is an analog of DA that is taken in by both the plasma membrane and intracellular vesicular transporters in catecholamine secreting cells. Several studies have reported the utility of FDA imaging in the diagnosis pheochromocytoma [104][105][106] . It has comparable results with MIBG in detecting non-metastatic pheochromocytomas but higher sensitivity for metastatic lesions [ 107 ] . ...
Pheochromocytomas and extraadrenal paragangliomas are functional tumors of the neuroendocrine system. They can secrete excessive amounts of catecholamines and although signs and symptoms may vary, generally they present as hypertension accompanied by sympathetic signs and symptoms. Plasma or urine metanephrines are reliable biochemical tests that are sensitive to detect patients with biochemically active tumors. CT-scan and MRI are anatomic imaging tests that remain vital for accurate pre-operative assessment. Functional imaging can be diagnostic and therapeutic; it enables detection of tumor extent and assesses possible response to therapy. Focus on genetic studies for familial predisposition for early detection is now at the forefront of research. Identification of SDHB mutations warrants aggressive treatment because of the propensity of these tumors for metastases with poor prognosis. Surgery remains the cornerstone of treatment with potential cure for benign tumors and palliative management. Long-term follow-up is necessary to detect recurrences and metastases. Malignancy still holds poor prognosis as therapeutic options remain limited. Radiopharmaceutical and chemotherapy remains promising but no major breakthroughs have been achieved. Palliative care and lesion-based treatment remains the standard.
... For instance, 123 I-metaiodobenzylguanidine (MIBG) scintigraphy has low sensitivity for the diagnosis of paragangliomas in patients with malignant PPGL and PPGL related to von Hippel-Lindau disease or with SDHx-related hereditary paraganglioma. 62,63 The sensitivity of 18 F-FDG-PET and 18 F-fluoro-L-DOPA ( 18 F-FDOPA) PET are also influenced by genetic status. Joint guidelines from the European Association of Nuclear Medicine and the Society of Nuclear Medicine have proposed an algorithm based on genetic status that can be used to choose the nuclear imaging modality. ...
Paragangliomas and phaeochromocytomas are neuroendocrine tumours whose pathogenesis and progression are very strongly influenced by genetics. A germline mutation in one of the susceptibility genes identified so far explains ∼40% of all cases; the remaining 60% are thought to be sporadic cases. At least one-third of these sporadic tumours contain a somatic mutation in a predisposing gene. Genetic testing, which is indicated in every patient, is guided by the clinical presentation as well as by the secretory phenotype and the immunohistochemical characterization of the tumours. The diagnosis of an inherited form drives clinical management and tumour surveillance. Different 'omics' profiling methods have provided a neat classification of these tumours in accordance with their genetic background. Transcriptomic studies have identified two main molecular pathways that underlie development of these tumours, one in which the hypoxic pathway is activated (cluster 1) and another in which the MAPK and mTOR (mammalian target of rapamycin) signalling pathways are activated (cluster 2). DNA methylation profiling has uncovered a hypermethylator phenotype in tumours related to SDHx genes (a group of genes comprising SDHA, SDHB, SDHC, SDHD and SDHAF2) and revealed that succinate acts as an oncometabolite, inhibiting 2-oxoglutarate-dependent dioxygenases, such as hypoxia-inducible factor prolyl-hydroxylases and histone and DNA demethylases. 'Omics' data have suggested new therapeutic targets for patients with a malignant tumour. In the near future, new 'omics'-based tests are likely to be transferred into clinical practice with the goal of establishing personalized medical management for affected patients.
... MIBG SPECT evaluated side-by-side with contrast-enhanced CT or MRI and hybrid imaging with SPECT/CT allow more accurate anatomical localization of areas of MIBG uptake, and thus contribute to the interpretation of equivocal findings and the reduction of falsenegative and/or false-positive results [51]. Relatively low sensitivity has also been reported in familial syndromes and malignant NENs, suggesting that there is low expression of catecholamine transporters or low affinity of MIBG for these transporters in the familial forms and in poorly differentiated malignant tumors [52]. ...
In the field of nuclear medicine, multiagent imaging can disclose enhanced expression of specific target molecules of neoplastic cells. This molecular information can be combined with the information provided by anatomical imaging. Over the past 20 years the use of radiolabeled somatostatin analogs as high-affinity tracers binding specifically to somatostatin receptors has allowed successful molecular imaging of neuroendocrine neoplasms (NENs), initially with single-photon-emitting radiopharmaceuticals, and subsequently also with positron-emitting radiopharmaceuticals. In this context, whole-body somatostatin receptor scintigraphy has changed the diagnostic and therapeutic approach to patients with NENs; moreover, somatostatin analog positron emission tomography (PET) tracers that allow higher spatial resolution imaging have recently been introduced. Nevertheless, several NENs can also be successfully imaged with radioagents that target the catecholamine pathway. Although radioiodinated meta-iodobenzylguanidine (MIBG) is traditionally the first option for radionuclide imaging and treatment of these NENs, the use of PET with 18F-l-dihydroxyphenylalanine is being increasingly reported, this approach showing several advantages over conventional imaging. Moreover, changes in tumor biology can be characterized by modifications in receptor or transporter expression on the cell membrane, and evidence has recently emerged that NENs expressing glucose transporters are more aggressive than tumors with low expression of glucose transporters. Therefore, [18F]FDG PET could provide prognostic information useful for stratifying patients according to their risk and for planning the correct therapy. The identification of new radiopharmaceuticals specific for different targets will constitute the basis not only of new diagnostic imaging approaches, but also of new therapeutic applications in NENs, besides radiolabeled peptide receptor radionuclide and 131I-MIBG therapy.
... 74 The poor performance of 131 I-MIBG in VHL tumors may be related to limited expression of NET in these patients. 127 In a subgroup analysis in the study by Timmers et al, both FDA PET and FDG PET had high sensitivity (82% and 83%, respectively) to detect metastatic SDHB tumors in comparison with the poor results using 18 F-DOPA (20%) and 123 I-MIBG (57%). 5 The reason for the discrepant results of the CA-specific molecules 18 F-DOPA and FDA, both utilizing the same amino acid transporter, ...
Abstract: Pheochromocytomas (PCs) and paragangliomas (PGLs) are routinely localized by
computed tomography (CT), magnetic resonance imaging (MRI), and metaiodobenzylguanidine (MIBG) scintigraphy. CT can identify tumors with high sensitivity but rather low specificity. MRI has higher sensitivity and specificity than CT and is superior to detect extra-adrenal disease. Radioiodinated MIBG scintigraphy has been used for more than 30 years and is based on MIBG uptake via the norepinephrine transporter on the cell membrane. The technique is very useful for whole-body studies in case of multiple primary tumors or metastases. Tumors with sole production of dopamine usually cannot be visualized with MIBG and may require positron emission tomographic (PET) studies with 18F-labeled radiotracers. Somatostatin receptor scintigraphy (SRS) using the radiolabeled somatostatin analog octreotide (based on the expression of the somatostatin receptors 2 and 5 by the tumor) can demonstrate PGL or metastases not visualized by MIBG. In this article, we review the use of MIBG scintigraphy to diagnose PC/PGL and compare the sensitivity and specificity with that of CT and MRI. We also describe the recent SRS and PET techniques and review the latest results of clinical studies by comparing these imaging modalities. Future perspectives of functional imaging modalities for PC/PGL are finally presented.
... Histopathology revealed a differentiated neuroendocrine tumor in the pancreas and a low-grade pheochromocytoma in the left adrenal gland the use of PET/CT in VHL disease. Kaji et al. reported that F- 18 fluorodopamine PET was useful in detecting VHL-related adrenal pheochromocytoma [13]. Kok et al. advocated the potential use of F-18 fluorodeoxyglucose PET/CT in a pancreatic neuroendocrine tumor in a VHL patient [14]. ...
Von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome with a variety of benign and malignant tumors such as retinal and central nervous system hemangioblastomas, endolymphatic sac tumors, renal cysts and tumors, pancreatic cysts and tumors, pheochromocytomas, and epididymal cystadenomas. Cross-sectional modalities (computed tomography and magnetic resonance imaging) as well as ultrasound play a major role in the initial evaluation and follow-up of the various manifestations of VHL disease. Ga-68-labeled somatostatin receptor analogs already have a significant role in the diagnosis, staging, and therapy management of neuroendocrine neoplasms and neural crest tumors. Herein, we report a case presenting a variety of malignancies in VHL and showing the usefulness of Ga-68 somatostatin receptor PET/CT as a one-stop-shop imaging modality in the management of VHL disease.
The incidence of pheochromocytoma in von Hippel-Lindau (VHL) disease varies based on specific genotype—approximately 20–30% overall. VHL patients should be screened from a young age, and management should involve multidisciplinary coordination of care. Timing, type of surgery, and surgical approach should be personalized to each patient and the manifestation of his or her disease, as VHL patients are at an increased risk for bilateral and multifocal pheochromocytomas, as well as tumors in the nearby kidney and pancreas. Close coordination between medical, surgical, and anesthesia teams is crucial in the perioperative period. Following resection, patients undergo lifelong surveillance for recurrent pheochromocytoma.
Recent advances in our understanding of the genetic and pathophysiologic mechanism of human malignancies have led to the recognition of frequent hereditary basis of many cancers. Hereditary cancer syndromes, which are now believed to cause up to 5% of human malignancies, are characterized by the early onset of various, multifocal, often advanced malignancies of usually more than one organ system. Frequently, multiple family members are involved. These hereditary cancer syndromes may pose specific diagnostic and therapeutic challenges, as they warrant contemporary paradigms for their screening protocols and targeted therapies. Here, we review imaging approaches to the most common hereditary cancer syndromes, including multiple endocrine neoplasia (MEN) syndromes, von Hippel-Lindau (VHL) syndrome, and Li-Fraumeni cancer syndrome.
Radioisotope-based molecular imaging (MI) techniques such as PET/CT and SPECT/CT aim to integrate patient-specific and disease-specific molecular information with traditional anatomical or structural imaging readouts. While [18F]FDG-PET/CT in oncology contributed to the commercial success of MI, hundreds of new agents have been investigated in the last three decades. At this time twelve PET and SPECT radiopharmaceuticals (based on 18F, 11C, 68Ga, 64Cu, and 123I) have been approved for routine clinical use and many more new radiopharmaceuticals are under active clinical investigation. These targeted imaging agents were designed to image different biochemical processes (such as glucose metabolism, membrane transport) and specific cellular targets in cancer cells (such as SSTR and PSMA). The objectives of MI include: the diagnosis of malignancy, detecting the primary tumor and metastatic burden, grading/staging malignancy, detecting the residual and/or tumor recurrence, guide radiation therapy, measure the response to therapy, and, finally, identify patients for specific targeted therapies. The tumor pathology and biology, the molecular basis of cancer, and the molecular targets specific for radiotracer development are discussed briefly. This chapter provides a description of radiopharmaceuticals in clinical use and presents a summary of the mechanisms and biochemical basis of localization of radiopharmaceuticals.KeywordsMolecular imagingFunctional imagingGlycolysisReceptor bindingTargeted radiopharmaceuticalMolecular targetRadiopharmaceuticalsPET/CT
Neuroendocrine neoplasms (NENs) are a heterogeneous group of epithelial neoplastic proliferations ranging from indolent well differentiated neuroendocrine tumors (NETs) to very aggressive poorly differentiated neuroendocrine carcinomas (NECs). The most characteristic feature of NENs is the homogeneous overexpression of peptide hormone receptors (such as somatostatin receptor, SSTR) on the tumor cell surface. The radio-theranostic concept of using a molecular marker (the targeting vehicle) for both molecular imaging and targeted radionuclide therapy has shown great promise of personalized medicine of patients with NETs. Radiolabeled SSTR agonists (111In-DTPA-octreotide, 68Ga-Dotatate, 68Ga-Dotatoc, 64Cu-Dotatate, 177Lu-Dotatate, and 177Lu-Dotatoc) are in routine clinical use for MI and TRT in patients with SSTR-2 positive NETs. Recent data indicates that radiolabeled SSTR antagonists (such as 68Ga/177Lu-NODAGA-JR11) may provide a better option for MI and therapy. Norepinephrine analog, 131I-MIBG (Azedra) is an ideal theranostic agent in patients with insufficient expression of SSTRs (such as neuroblastoma, pheochromocytoma, and paraganglioma). Several new radiotracers targeting glucagon-like peptide-1 (GLP-1) receptor, chemokine receptor-4 (CXCR4), and cholecystokinin-2 (CCK2) receptors are under active clinical investigation. This chapter provides a broad overview of the current approaches and future challenges of diagnostic and therapeutic evaluations in NENs. Theranostics in NETs serves as a model for developing targeted probes for several other cancers.KeywordsNeuroendocrine tumor (NET)TheranosticsSomatostatin receptor (SSTR)SSTR agonistsOctreotide analogsNorepinephrine transporterNeuroblastomaPheochromocytomaTargeted radionuclide therapy (TRT)
Molecular imaging evaluation of pheochromocytomas and paragangliomas depends on multiple factors, such as localized versus metastatic disease, the genetic, and biochemical profile of tumors. Positron emission tomography/computed tomography (PET/CT) imaging of these tumors outperforms Meta-Iodo-Benzyl-Guanidine (MIBG) scintigraphy in most cases. A few PET radiotracers have been studied in evaluating these patients with somatostatin receptor PET imaging and have shown superior performance compared with other agents in most of these patients. 18F-fluorodeoxyglucose PET/CT imaging is useful in select patients, such as those with succinate dehydrogenase complex subunit B-associated disease. Treatment strategy depends on multiple factors and necessitates a multidisciplinary approach.
MIBG scintigraphy in pheochromocytomas and paragangliomas can be performed using different radioiodine isotopes. 123I is preferred for imaging due to better quality characteristics and lower radiation dosimetry but 131I is more available and less costly. Nodal disease or liver disease has a lower MIBG scintigraphy detection sensitivity, as well as, SDHB or other gene mutations may be related to false-negative scans. General specificity is around 82% while sensitivity is around 88% for pheochromocytomas and 67% for paragangliomas. Discrimination from adrenal hyperplasia may also pose a difficulty causing false-positive results.KeywordsPheochromocytomasParagangliomasScintigraphyMIBG
6-[¹⁸F]Fluorodopamine (6-[¹⁸F]FDA) proved valuable as a diagnostic tool for neuroendocrine and rare tumors, such as ganglioneuromas and pheochromocytomas, however, clinical application is still limited. So far, its radiosyntheses were impeded by the formation of side-products, low molar activity, multi-step reactions and the use of challenging precursors. Here, we describe a detailed enzymatic procedure for fast, simple and high yield synthesis of no carrier added 6-[¹⁸F]FDA from 6-[¹⁸F]FDOPA with high radiochemical yield of ~69 % and >95 % purity as determined by radio-HPLC and -TLC. The product formulation was stable and suitable for in vivo application.
The aim of this chapter is to report the indications and data on efficacy and toxicity of radionuclide therapy in pediatric patients, highlighting the precautions that have to be taken as compared to adult patients.
In particular, children with Neuroblastoma (NB), the most common extracranial tumor of pediatric age, may refer with a metastatic disease at diagnosis in 50% of cases. ¹²³I-meta-iodobenzylguanidine (m-IBG) scintigraphy is a “corner stone” in the diagnosis, staging and restaging of NB. The therapeutic approach for high-risk NB includes induction chemotherapy, followed by surgery and myelo-ablative chemotherapy associated to autologous hematopoietic stem cell transplantation. ¹³¹I-mIBG therapy is indicated in high-risk NB patients with persistence of mIBG-avid metastatic disease, and has an overall response of 30%.
The toxicity can include gastrointestinal distress and tachycardia during the infusion, hematologic toxicity in the weeks following the administration, and long-term hypothyroidism or secondary malignancies. Precautions include symptomatic management of symptoms during the infusion (antiemetics, beta-blockers), careful monitoring of blood values with substitution of red blood cells/platelet or autologous stem cells infusion whenever needed, and thyroid blockade. Patients should be always monitored for the insurgence of secondary tumor, such as papillary thyroid cancer.
Other frequent cancers in children are malignant pheochromocytomas (PCCs) and paragangliomas (PPGs) that originate in the adrenal medulla and in the extra-adrenal ganglia; malignancy occurs in 10% of PCCS and 20–40% of PPGs. For these tumors ¹²³I-mIBG whole-body scan has a relevant diagnostic role. ¹³¹I-MIBG therapy is indicated in all cases with inoperable PPCs and PPGs; in addition, patients with metastatic disease, in course of progression and/or intractable, can be considered eligible for mIBG therapy.
The toxicity includes gastrointestinal, hematological, and endocrine side effects (as observed in the NB scenario), more serious complications include renal damage of respiratory distress. Precautions include symptomatic treatments of acute side effects, hematologic substitution, and generous hydration.
Children and young adults may also develop differentiated thyroid cancer (DTC). Differently from adults, pediatric DTC may present diffuse infiltrative pattern throughout the thyroid gland and can be more frequently associated to extensive lymph node and lung metastastization. Thyroidectomy is the principal therapeutic approach and ¹³¹I radionuclide therapy is an important therapeutic option especially for those patients at intermediate- or high-risk of disease relapse/persistence after surgery.
The toxicity is usually mild and includes temporary salivary dysfunction, gastrointestinal distress, hematological parameters drop, gonadal damage, and, in patients with extensive lung localizations, pulmonary fibrosis.
Precautions include vigorous hydration, administration of candies to stimulate the salivary flow, and symptomatic treatment of the gastroenteric side effects. Sperm banking can be considered in young male patients receiving high activities. The hematological side effects are usually self-resolving. Dosimetry approaches should be used in patients with diffuse lung involvement, as the pulmonary fibrosis is strictly dose-dependent.
Evaluating the adrenal gland with imaging can be challenging. The adrenal glands may be morphologically within normal limits even in the presence of clear hyperfunction. Hyperplasia and small nodules may coexist. Non-functioning nodules are frequent and need to be differentiated from hyperfunctioning adenomas or malignancy. However, the high-resolution anatomical imaging provided by computed tomography (CT) and magnetic resonance imaging (MRI), together with the functional characterization afforded by radionuclide imaging, allows correlation with clinical and endocrine parameters. The use of these modalities in various adrenal disorders is detailed with illustrative images. In this chapter, the anatomy of the adrenal glands is reviewed, while imaging modalities in common modern use are described with their advantages and limitations.
The optimal treatment strategy for patients with small non-functioning VHL-related incidentalomas is unclear. We searched the Freiburg VHL registry for patients with radiologic evidence of pheochromocytoma/paraganglioma (PHEO/PGL). 176 patients with single, multiple, and recurrent tumors were identified (1.84 tumors/patient, range 1-8). Mean age at diagnosis was 32±16 years. 74% of tumors were localized to the adrenals. Mean tumor diameter was 2.42±2.27 cm, 46% were <1.5 cm. 24% of tumors were biochemically inactive. Inactive tumors were significantly smaller than active PHEO/PGL at diagnosis (4.16±2.80 cm vs. 1.43±0.45 cm; p<0.025) and before surgery (4.89±3.47 cm vs. 1.36±0.43 cm; p<0.02). Disease was stable in 67% of 21 patients with evaluable tumors ≤1.5 cm according to RECIST and progressed in 7. Time till surgery in these patients was 29.5±20.0 months. 155 patients underwent surgery. PHEO/PGL was histologically excluded in 4 and proven in 151. Of these one had additional metastatic disease, one harboured another tumor of a different type, and in 2 a second surgery for suspected disease recurrence did not confirm PHEO/PGL. Logistic regression analysis revealed 50% probability for a positive/negative biochemical test result at 1.8 cm tumor diameter. Values of a novel symptom score were positively correlated with tumor size (Rs 0.46, p<0.0001) and together with a positive biochemistry a linear size predictor (p<0.01). Results support standardized clinical assessment and measurement of tumor size and metanephrines in VHL patients non-functioning incidentalomas <1.5 cm at one year following diagnosis and at individualized intervals thereafter depending on evolving growth dynamics, secretory activity and symptomatology.
With the development of Positron Emission Tomography (PET) technology, a variety of PET imaging agents labeled with radionuclide ¹⁸F have been developed and widely used in the diagnosis and treatment of various clinical diseases in recent years. For example, they have showed a great value of study in the field of tumor detection, tumor treatment and evaluation of tumor therapy in a non-invasive, qualitative and quantitative way. In this review, we highlight the recent development in chemical synthesis, structure and characterization, imaging characterization, and potential applications of these ¹⁸F labeled small molecule PET imaging agents for the past 5 years. The development and application of ¹⁸F labeled small molecules will expand our knowledge of the function and distribution of diseases-related molecular targets and shed light on the diagnosis and treatment of various diseases including tumors.
The human norepinephrine transporter (hNET) is a transmembrane protein responsible for reuptake of norepinephrine in presynaptic sympathetic nerve terminals and adrenal chromaffin cells. Neural crest tumors, such as neuroblastoma, paraganglioma and pheochromocytoma often show high hNET expression. Molecular imaging of these tumors can be done using radiolabeled norepinephrine analogs that target hNET. Currently, the most commonly used radiopharmaceutical for hNET imaging is meta-[123I]iodobenzylguanidine ([123I]MIBG) and this has been the case since its development several decades ago. The γ-emitter, iodine-123 only allows for planar scintigraphy and SPECT imaging. These modalities typically have a poorer spatial resolution and lower sensitivity than PET. Additional practical disadvantages include the fact that a two-day imaging protocol is required and the need for thyroid blockade. Therefore, several PET alternatives for hNET imaging are actively being explored. This review gives an in-depth overview of the current status and recent developments in clinical trials leading to the next generation of clinical PET ligands for imaging of hNET-expressing tumors.
Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors, a large proportion of which secrete catecholamines. PPGL are associated with a high cardiovascular morbidity and come with a risk of malignancy. The therapy of choice is surgical resection. Nevertheless, PPGL are associated with a lifelong risk of tumor persistence or recurrence. Currently, there are no clinical, biochemical, histopathological or imaging characteristics, which can predict or exclude malignant behavior or tumor recurrence. Therefore, long-term follow-up is recommended even after apparent complete surgical removal. Early detection of recurrence is essential to reduce cardiovascular morbidity and mortality due to catecholamine secretion, to prevent morbidity by mass effects of paraganglioma (PGL) or by metastatic spread of disease.
Due to the rarity of these tumors, no prospective data on long-term surveillance exist. In fact, current recommendations are based on retrospective analyses, expert opinions and case studies. The aim of this review is to provide an overview on the current state of knowledge with regard to known factors that increase the risk of recurrence and might impact disease monitoring as well as the available possibilities for biochemical and imaging follow-up. Based on this overview, we aim to propose a practical approach for a patient-oriented follow-up after surgical removal of a PPGL.
Thyrotoxicosis represents a clinical condition that results from excess thyroid hormone(s) levels and action in peripheral tissues, either with or without increased synthesis of thyroid hormone(s) by the gland. It has multiple different etiologies and potential therapies; therefore, an accurate diagnosis is mandatory for appropriate treatment. 131-Radioiodine has been used since 1941 to cure hyperthyroidism due to toxic thyroid disease [diffuse or (multi)-nodular]. From its first use, millions of people have been treated worldwide and today it represents the first example of “theranostic” radiotracer [(−ve)-beta electrons to obtain the therapeutic effect, gamma-emission to show its distribution in the gland]. 131-Radioiodine therapy has two main aims: the first is to correct hyperthyroidism (by fixed or calculated dose) reaching a euthyroid state [the optimal result for patients affected by (multi)-nodular toxic disease] or a hypothyroid state (the optimal result for patients with diffuse toxic disease); the second is to reduce whole gland or toxic (multi)-nodular volume. Despite RAI therapy being a safe and generally well-tolerated treatment, either acute or late side effects (e.g., radiation thyroiditis, sialadenitis, worsening or appearance of orbitopathy) may occur, principally related to insufficient clinical control of hyperthyroidism and active thyroid orbitopathy due to Graves’ disease. The purpose of this chapter is to provide advice to nuclear medicine physicians in evaluating patients with benign thyroid disease for 131-radioiodine therapy. Diagnosis of hyperthyroidism and clinical management, along with advantages, optimal activities, and possible side effects of 131-radioiodine therapy, are discussed.
6‐[18F] fluorodopamine ([18F]F‐DA) is taken into cells via the norepinephrine transporter (NET). Recent [18F]F‐DA PET‐CT imaging of adult neuroendocrine tumors shows a dramatic improvement in sensitivity over the standard‐of‐care, meta‐iodobenzylguanidine (MIBG) SPECT‐CT. A new precursor (ALPdopamine™) allows no‐carrier‐added synthesis resulting in high molar activity [18F]F‐DA. Automated synthesis of [18F]F‐DA was performed in a single reactor using a two‐step procedure; fluorination and thermolysis of a diaryliodonium salt precursor followed by acid hydrolysis. Phase transfer agents, Kryptofix® 222 and two tetraalkylammonium salts, were investigated. Optimized synthesis of [18F]F‐DA was achieved in 56‐60 minutes (26% EOS, non‐decay corrected). The product passed all FDA‐required quality control testing for human use. Accumulation of [18F]F‐DA in the SK‐N‐BE(2)‐C (high NET expression) cells was significantly higher than in SH‐EP (minimal NET expression) cells (p < 0.0001). ALPdopamineTM provides an effective scaffold for the routine production of [18F]F‐DA for human use. Validation of uptake by neuroblastoma (NB) cell lines supports the use of [18F]F‐DA for imaging NB patients. A pediatric NB imaging trial using [18F]F‐DA PET has been approved (IND #138638) based on the methods reported here. We expect [18F]F‐DA will be localized in NB tumors and that high quality functional images will be obtained within minutes after injection.
Metaiodobenzylguanidine (MIBG) a guanithidine analogue, labelled with 123I and 131I, is used for imaging and therapy of neuroblastomas and various neural crest tumors like paragangliomas, pheochromocytomas, medullary cancer of thyroid and carcinoids since the past three to four decades. In this review article, we shall revisit MIBG as a radiopharmaceutical and its various applications in neural crest tumors.
Pheochromocytomas and paragangliomas (PPGLs) are highly variable with respect to clinical presentation, endocrine phenotype, growth rate, and metatastatic potential. This relates to a large genetic diversity and related pathways of tumorigenesis. By applying a multi-omics approach, profound abnormalities in tumor cell metabolism related to mitochondrial defects in a subset of PPGLs have been identified.
Besides tumor localization, radionuclide imaging has been shown to be very useful for the functional characterization of PPGL and can be regarded as a tool for noninvasive and immediate in vivo metabolomics. Different genotypes underlying these tumors can be distinguished by 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and other PET tracers. This is achieved by quantitation of 18 F-FDG uptake and kinetics, identifying succinate dehydrogenase (SDH)-deficient PPGLs that are prone to malignant tumor behavior. Thereby radionuclide imaging facilitates the stratification of these tumors and can guide tailor-made and individualized diagnostic and therapeutic strategies.
Pheochromocytomas and extra-adrenal paragangliomas, associated with the sympathetic nervous system, are rare neuroendocrine tumors of neural crest origin. These tumors behave differently from those associated with the parasympathetic system (i.e., head and neck paragangliomas). This chapter will particularly emphasize current and emerging knowledge of imaging options in these tumors.
Zur Anwendung der PET-Untersuchung bei den malignen endokrinen Tumoren liegen für das Kindesalter fast ausschließlich Fallberichte vor. Studien, die eine größere Zahl an Patienten einschließen, gibt es aufgrund der Seltenheit der Tumoren zumeist lediglich für Erwachsene
The confirmation of somatostatin receptor (SSTR) expression in tumors deriving from chromaffin tissue starts to influence the approach to pheochromocytomas and paragangliomas (PPGLs). In vitro studies have revealed SSTR expression, particularly subtypes 2A and 3, in PPGLs, the confinement of which to cell membranes is essential for successful diagnostic use of somatostatin analogues. Scintigraphy with radiolabeled somatostatin analogues is nowadays an approved complementary method for the localization of PPGLs, particularly malignant head and neck PGLs, and, if necessary, for qualification for PRRT and follow-up of the patients.
Neuroendocrine tumors (NETs) originate from single or clustered neuroendocrine cells, distributed in the gastrointestinal tract, urogenital tract, endocrine, and bronchopulmonary system. NETs account for approximately 2.2% of all malignancies. These slow growing tumors are difficult to localize and often metastatic at diagnosis. Surgery can be curative in only 20% of cases. A syndrome of flushing, diarrhea, sweating, and bronchospasm due to secretion of multiple hormones (carcinoid syndrome) occurs in 20% of patients. Most NETs are sporadic, but occasionally, they may be part of inherited syndromes, known as multiple endocrine neoplasia type 1 and 2 (MEN1 and MEN2). The European Neuroendocrine Tumor Society diagnostic and prognostic stratification criteria are based on histological typing, differentiation, grading, and TNM staging. Immunostaining for the neuroendocrine markers synaptophysin and chromogranin and for the proliferation marker Ki67/MIB1 is mandatory, while immunostaining for hormones, receptors, and other markers is optional. The grading proposal stratifies tumors in G1 (1 mitotic count/10 HPF, Ki67≤2%), G2 (2–20 mitotic counts/10 HPF, Ki67: 3–20%), and G3 (mitotic count >20/10 HPF, Ki67 > 20%). The tumor grading, together with histopathology type and staging, reflects the potential metastatic spread and, therefore, has an impact on the therapy options (surgery, biotherapy, and chemotherapy). CT, MRI, and radionuclide imaging of somatostatin receptor expression or catecholamine uptake is helpful to localize the lesions. Somatostatin receptor imaging utilizes 111In-pentetreotide (OctreoScan®), or 68Ga-octreotide, while catecholamine uptake is usually imaged with 123I-metaiodobenzylguanidine (131I-MIBG). [18F]FDG PET/CT is less useful than somatostatin/catecholamine receptor imaging. Main indications for radionuclide imaging of NETs are for localization (also as a guide to surgery), for staging, for assessing response to therapy, and for selecting patients for possible therapy with radiolabeled somatostatin analogues or with 131I-MIBG. Peptide receptor radionuclide therapy (PRRT) uses high doses of radiolabeled peptides to treat unresectable or metastasized NETs.
Computed tomography (CT) and magnetic resonance imaging (MRI) are the major imaging modalities used for the localization of catecholamine-producing tumors (pheochromocytoma and paraganglioma). Functional imaging (FI) offers an alternative approach to localize, evaluate, and stage these tumors. Our objective was to describe the additive benefit of FI studies for patients with pheochromocytoma and paraganglioma (PPG) who have undergone MRI or CT scan evaluation. We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus from database inception through June 2012 for studies that included patients with biochemically proven PPGs who underwent CT or MRI and additional FI for the localization of PPGs. We included 32 studies enrolling a total of 1,264 patients with a mean age of 43-years old. The studies were uncontrolled and evaluated six FI modalities. FI tests provided small additive value to CT/MRI, aiding in the localization of only 24/1,445 primary cases (1.4 %) and 28/805 metastatic cases (3.5 %). In metastatic cases, 6-[F-18]fluoro-L-dihydroxyphenylalanine (DOPA) and fluorodopamine-PET (FDA) were the FI tests most successful at identifying disease missed by CT/MRI, providing additional benefit in 6/60 (10 %) and 5/78 (6.4 %) cases, respectively. No clinically significant findings were observed in any of the predefined subgroups. No study evaluated the impact of FI on the completeness of surgical resection or other patient-important outcomes. Observational evidence suggests that FI tests have a limited additional role in patients with PPGs who have undergone CT/MRI evaluation. However, the role of FI tests in specific subgroups of patients with atypical presentations (metastatic, extra-adrenal) as well as the use of hybrid FI tests should be explored. Further research should also evaluate the impact of FI tests on patient-important outcomes.
Improvements in medical imaging have resulted in the incidental discovery of many silent and unrecognized adrenal tumors. The term “adrenal incidentaloma” (AI) is applied to any adrenal mass ≥ 1 cm in its longest axis that is discovered incidentally during abdominal imaging that was not performed to specifically evaluate adrenal pathology. These incidentalomas may be either secretory or non-secretory, benign or malignant. Distinctive characteristics of these lesions must be determined by the clinician to determine appropriate management. Such distinctions are based on laboratory findings and imaging, principally CT with and without contrast injection. Investigations must be carefully chosen to avoid ordering unnecessary and expensive tests for too many patients while, at the same time, avoiding the risk of failing to diagnose a malignant or secreting tumor. These examinations will determine patient care: surgery or surveillance. When simple surveillance is chosen, specific criteria must be met with regard to diagnostic modalities (clinical, imaging, laboratory testing) and its duration.
Improvements in medical imaging have resulted in the incidental discovery of many silent and unrecognized adrenal tumors. The term “adrenal incidentaloma” (AI) is applied to any adrenal mass ≥ 1 cm in its longest axis that is discovered incidentally during abdominal imaging that was not performed to specifically evaluate adrenal pathology. These incidentalomas may be either secretory or non-secretory, benign or malignant. Distinctive characteristics of these lesions must be determined by the clinician to determine appropriate management. Such distinctions are based on laboratory findings and imaging, principally CT with and without contrast injection. Investigations must be carefully chosen to avoid ordering unnecessary and expensive tests for too many patients while, at the same time, avoiding the risk of failing to diagnose a secreting malignant or tumor. These examinations will determine patient care: surgery or surveillance. When simple surveillance is chosen, specific criteria must be met with regard to diagnostic modalities (clinical, imaging, laboratory testing) and its duration.
Localization of phaeochromocytomas and paragangliomas (PPGLs) should involve functional imaging since anatomical imaging modalities can either fail to locate the tumor or can be suboptimal due to an anatomical abnormality or previous surgery. Functional imaging is particularly useful to fully delineate the extent of disease by using the whole body scan and the evaluation of multifocality, metastatic or recurrent disease. An increasing number of radiolabeled tracers have become available for tumor visualization during the past decade. (123) I-meta-iodobenzylguanidine scintigraphy is the most widely used functional imaging modality and its sensitivity to identify chromaffin cell tumors varies from 85-88% for phaeochromocytomas and 56-76% for paragangliomas, while specificity ranges between 70-100% and 84-100%, respectively. This article is protected by copyright. All rights reserved.
To compare 123I-metaiodobenzylguanidine (MIBG) and [Fluorine-18]-2-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET) in 22 patients with phaeochromocytomas and paragangliomas (PGL) retrospectively and to evaluate the correlation between FDG uptake and Ki-67 proliferative index. Fourteen of 17 (82%) patients at initial diagnosis had positive FDG uptake, more intensely in PGL. Eleven of 12 (92%) patients had positive MIBG uptake. PET and MIBG scintigraphy were concordant in 10 patients, discordant in 6. Combined results yielded no false negative findings and are complementary. Neither maximum standardised uptake value nor visual scores on MIBG correlated with Ki-67.
Aim:
The aim of this paper was to systematically review published data about the comparison of radiolabelled metaiodobenzylguanidine (MIBG) scintigraphy and positron emission tomography (PET) with different radiopharmaceuticals in patients with pheochromocytoma and paraganglioma (Pheo/PGL).
Methods:
A comprehensive literature search of studies published in PubMed/MEDLINE and Embase databases through September 2012 and regarding MIBG scintigraphy and PET imaging with different radiopharmaceuticals in patients with Pheo/PGL was carried out.
Results:
Twenty-eight studies comprising 852 patients who underwent both MIBG scintigraphy and PET or PET/CT with different radiopharmaceuticals were included and discussed. Three studies evaluated carbon-11-hydroxyephedrine ([11C]HED) as PET radiopharmaceutical, nine studies fluorine-18-dopamine ([18F]DA), eight studies fluorine-18-dihydroxyphenylalanine ([18F]DOPA), twelve studies fluorine-18-fluorodeoxyglucose ([18F]FDG) and five studies gallium-68-somatostatin analogues.
Conclusions:
Despite the heterogeneity of the studies included in the analysis, it can be concluded that the diagnostic performance of PET with various agents is clearly superior to that of MIBG scintigraphy in patients with Pheo/PGL, mainly for familial, extra-adrenal and metastatic diseases; however, MIBG maintains a unique role in selecting patients suitable for 131I-MBG therapy. Further larger prospective studies comparing MIBG and different PET tracers in patients with Pheo/PGL as well as a cost-effectiveness analysis of the two techniques are needed.
Pheochromocytomas and paragangliomas are tumors arising from neural crest-derived cells. They can be sympathetic in origin, catecholamine secreting and located in the abdomen or chest, or parasympathetic, generally non-secreting and located in the head and neck region. It is well established that about 35% of them are genetically determined. Germ-line mutations in one of the 10 so far known susceptibility genes is especially suspected when the tumors are diagnosed in young patients, multiple or recurrent or associated with additional lesions typical of syndromic clinical pictures such as von Hippel-Lindau, Multiple Endocrine Neoplasia type 2 or Neurofibromatosis type 1. Tumor genetic profile determines the type and pattern of catecholamine release, the clinical presentation, the risk of malignancy and may influence the choice of the radiotracers used in functional imaging, the type of surgical procedures as well as the type of medical therapy in the treatment of metastatic disease.
Metaiodobenzylguanidine (MIBG) locates most pheochromocytomas and neuroblastomas. The tracer is concentrated in intracellular storage vesicles by an active process. Many other neuroendocrine tumors of the amine precursor uptake and decarboxylation (APUD) series have hormonal storage vesicles and, thus, the potential to take up [131I]MIBG. A variety of neuroendocrine tumors in 57 patients were studied 1, 2, and 3 days after 0.5 mCi [131I]MIBG. Views from skull to pelvis were obtained. Results of MIBG scans were compared with all available imaging modalities (including plain radiography, liver scan, ultrasound, computed tomography, and angiography) and surgical exploration. The neuroendocrine nature of the tumor was determined by histology, immunohistochemistry, electron microscopy, and the assay of appropriate biogenic amines and peptide hormones. Results were (positive/total cases): carcinoids (four of ten), nonsecreting paragangliomas (three of three), sporadic medullary carcinomas of the thyroid (MCT) (one of five), familial MCT (one of 26), chemodectomas (two of five), oat cell carcinomas (zero of four), choriocarcinoma (one of one), atypical schwannoma (with storage granules) (one of one), Merkel cell skin cancer (one of one), islet cell carcinoma (zero of one). We conclude that a wide range of neuroendocrine tumors show [131I]MIBG uptake; tumors other than pheochromocytomas and neuroblastomas are less often seen scintigraphically, but in certain cases (e.g., carcinoid and nonsecreting paragangliomas) scintigraphy may be useful in depicting the extent and location of disease and may indicate therapeutic potential. Iodine-131 MIBG shows promise in the diagnosis and staging of tumors of varied types.
The detection of pheochromocytomas in patients at risk for these tumors, such as patients with von Hippel-Lindau disease or multiple endocrine neoplasia type 2 (MEN-2), is hindered by the inadequate sensitivity of commonly available biochemical tests. In this study we evaluated measurements of plasma normetanephrine and metanephrine for detecting pheochromocytomas in patients with von Hippel-Lindau disease or MEN-2.
We studied 26 patients with von Hippel-Lindau disease and 9 patients with MEN-2 who had histologically verified pheochromocytomas and 50 patients with von Hippel-Lindau disease or MEN-2 who had no radiologic evidence of pheochromocytoma. Von Hippel-Lindau disease and MEN-2 were diagnosed on the basis of germ-line mutations of the appropriate genes. The plasma concentrations of normetanephrine and metanephrine were compared with the plasma concentrations of catecholamines (norepinephrine and epinephrine) and urinary excretion of catecholamines, metanephrines, and vanillylmandelic acid.
The sensitivity of measurements of plasma normetanephrine and metanephrine for the detection of tumors was 97 percent, whereas the other biochemical tests had a sensitivity of only 47 to 74 percent. All patients with MEN-2 had high plasma concentrations of metanephrine, whereas the patients with von Hippel-Lindau disease had almost exclusively high plasma concentrations of only normetanephrine. One patient with von Hippel-Lindau disease had a normal plasma normetanephrine concentration; this patient had a very small adrenal tumor (<1 cm). The high sensitivity of measurements of plasma normetanephrine and metanephrine was accompanied by a high level of specificity (96 percent).
Measurements of plasma normetanephrine and metanephrine are useful in screening for pheochromocytomas in patients with a familial predisposition to these tumors.
The purpose of the study was to assess the diagnostic utility of 6-[(18)F]-fluorodopamine ([(18)F]-DA) positron emission tomography scanning (PET) vs. [(131)I]-metaiodobenzylguanidine (MIBG) scintigraphy in patients with metastatic pheochromocytoma (PHEO). We studied 10 men and six women (mean age 38.2 +/- 11.5 yr) referred to our institution for metastatic PHEO; two patients were studied twice within a 2-yr interval. Imaging modalities included computed tomography (CT), magnetic resonance imaging (MRI), [(131)I]-MIBG scintigraphy, and [(18)F]-DA PET. Fifteen of 16 patients had positive findings on CT and/or MRI consistent with the presence of pheochromocytoma. [(18)F]-DA PET was positive in all patients, but seven patients had negative [(131)I]-MIBG scans. Thirty-eight foci of uptake were shown by both [(18)F]-DA PET and [(131)I]-MIBG scintigraphy, 90 only by [(18)F]-DA PET, and 10 only by [(131)I]-MIBG; most lesions were also visible on CT/MRI. In this initial series of patients with metastatic pheochromocytoma, [(18)F]-DA PET localized PHEO in all patients and showed a large number of foci that were not imaged with [(131)I]-MIBG scintigraphy. Thus, [(18)F]-DA PET was found to be a superior imaging method in patients with metastatic PHEO, in which correct detection of disease extension often determines the most appropriate therapeutic plan and future follow-up.
The 11C-labeled tracer meta-hydroxyephedrine (11C-HED) is a noradrenaline analog that was developed to visualize the sympathetic nervous system with PET. Initial clinical studies show a rapid uptake of 11C-HED in localized tumors of this system. Whole-body imaging with 11C-HED PET is now possible as PET/CT scanners allow a rather short examination time. The aim of this study was to evaluate the feasibility of whole-body 11C-HED PET/CT for examination of tumors of the sympathetic nervous system and to directly compare the results with 123I-labeled meta-iodobenzylguanidine (123I-MIBG) scintigraphy, including SPECT/CT.
In 19 consecutive patients, 9 mo to 68 y old (median, 32 y), 24 whole-body 11C-HED PET/CT (low-dose CT) examinations were performed. Scans were compared with attenuation-corrected 123I-MIBG SPECT/CT scans (24-h scan, low-dose CT). The intensity of tracer accumulation above background was visually analyzed in both scans, PET and SPECT, using a 4-value scale. In 11C-HED PET, mean and maximum standardized uptake values were determined for all lesions.
In 14 patients with 19 pairs of examinations, the following tumors were confirmed histologically: 6 neuroblastomas, 5 pheochromocytomas, 1 ganglioneuroblastoma, and 2 paragangliomas. In 5 patients, each having 1 pair of examinations, clinical follow-up and/or histologic examination did not reveal any tumor deriving from the sympathetic nervous system. 11C-HED PET/CT detected 80 of 81 totally depicted tumor lesions (sensitivity, 0.99; soft tissue, 61; bone, 19). 123I-MIBG SPECT/CT detected 75 of 81 lesions (sensitivity, 0.93; soft tissue, 56; bone, 19). With both methods, there were no false-positive lesions. The tumor-to-background contrast of 11C-HED uptake was higher in comparison with 123I-MIBG uptake in 26 lesions (0.32; soft tissue, 18; bone, 8), equal in 39 lesions (0.48; soft tissue, 30; bone, 9), and lower than 123I-MIBG uptake in 16 lesions (0.20; soft tissue, 14; bone, 2).
Whole-body imaging using 11C-HED PET/CT is feasible in the clinical setting of patients with tumors of the sympathetic nervous system. 11C-HED PET/CT detected more tumor lesions than 123I-MIBG SPECT/CT. However, tumor-to-background contrast of 11C-HED in lesions can be higher, equal, or lower compared with 123I-MIBG.
Radiolabelled meta-iodobenzylguanidine (MIBG) is widely used in the diagnosis, follow-up and treatment of patients with tumours of neural crest origin. Some commonly prescribed and readily available over-the-counter medicines interfere with the uptake and biodistribution of this radiopharmaceutical. This may lead to poor concentration of radiolabelled MIBG within the target organs and tissues. The clinical implications are a potentially inaccurate assessment of tumour burden during diagnostic studies and a suboptimal radiation dose when MIBG is employed for targetted radiotherapy. In order to avoid false negative results a comprehensive list of prescribed and over-the-counter medicines that have the potential to inhibit uptake of MIBG has been compiled. It is hoped that this will help nuclear medicine physicians to avoid this pitfall.
To ascertain the magnetic resonance (MR) imaging characteristics of pheochromocytomas and paragangliomas and to compare MR with computed tomography (CT) and iodine-131 metaiodobenzylguanidine (I-131 MIBG), 19 patients (18 with pheochromocytomas, one with a paraganglioma) were studied. The 18 patients with pheochromocytomas had had positive findings with I-131 MIBG scintigraphy. Abdominal pheochromocytomas were generally hypointense compared with normal liver on T1-weighted MR images and extremely hyperintense on T2-weighted MR images. MR imaging was preferable to CT in the evaluation of primary pheochromocytomas due to superior tissue characterization, particularly in the patient with hypertension and borderline catecholamine levels. For patients with recurrent or metastatic disease, the data suggest that I-131 MIBG scintigraphy is the examination of choice.
Four patients with von Hippel-Lindau disease had clinically silent adrenal nodules; in three of them, detailed evaluation and observation showed pheochromocytoma.
In patients with von Hippel-Lindau disease multiple bilateral adrenal pheochromocytoma can develop, which has traditionally been treated with adrenalectomy. Partial adrenalectomy can preserve normal adrenal function and avoid the morbidity associated with medical adrenal replacement. We demonstrate whether adrenal function could be preserved by partial adrenalectomy in patients with von Hippel-Lindau disease.
From 1995 to 1998, 13 consecutive von Hippel-Lindau disease patients with pheochromocytoma underwent 14 partial and 6 complete unilateral adrenalectomies. Function of residual normal adrenal and recurrence of adrenal pheochromocytoma were determined at followup.
Of the patients 2 had undergone unilateral adrenalectomy and 1 had undergone complete and partial adrenalectomy previously. Following surgery residual normal adrenal tissue consisted of 1 partial adrenal in 3 patients, bilateral partial adrenal in 5, partial and complete adrenal gland in 1, 1 complete adrenal gland in 3 and no adrenal tissue in 1. Three patients with residual adrenal tissue were placed on medical adrenal replacement until adrenocorticotropic hormone stimulation testing demonstrated adrenocortical function. In 2 patients 1 adrenal and 2 extra-adrenal new pheochromocytomas developed 11 and 152 months, respectively, after partial adrenalectomy. No morbidity related to pheochromocytoma was observed during followup.
Partial adrenalectomy can preserve adrenal function in patients with a hereditary form of pheochromocytoma.
Patient with pheochromocytoma (PCT) cannot be cured without operation, therefore, preoperative determination of the localization of PCT should be performed accurately. [131I]-Metaiodobenzylguanidine (MIBG) scintigraphy is a gold standard for the diagnosis of PCT. However, [123I]-MIBG is also found to accumulate in PCT. In order to clarify the usefulness of [123I]-MIBG scintigraphy for the local detection of PCT, we compared the distribution of [123I]- and [131I]-MIBG in patients with or without PCT.
[131I]- and [123I]-MIBG scintigraphy was performed in 29 and 16 patients, respectively. In the former group, 14 patients had PCT, 12 had hypertension without any adrenal disorder and three had other diseases. In the latter group, eight patients had PCT, two had hypertension without any adrenal disorder and six had other diseases. The sensitivity, specificity and accuracy of [123I]-compared with [131I]-MIBG scintigraphy were compared.
The sensitivity of [131I]- and [123I]-MIBG scintigraphy was 85.7 and 90%, respectively. The specificity of each test was 100%. The accuracy of [131I]- and [123I]-MIBG scintigraphy was 93.1 and 95%, respectively. The quality of images obtained using [123I]-MIBG was better than with [131I]-MIBG, because [123I]-MIBG generated a higher dose of gamma-rays with a higher specificity than [131I]-MIBG. In addition, normal adrenal grands were visualized in 50% of patients tested with [123I]-MIBG scintigraphy.
These results indicate that [123I]-MIBG scintigraphy is a valuable tool for the local detection of PCT, as is [131I]-MIBG scintigraphy. Furthermore, it is possible that [123I]-MIBG can be used as an alternative to [131I]-MIBG for the detection of PCT. Our study was not a prospective study and the background of the patients was not matched. Further prospective studies are needed in order to determine the efficacy of [123I]-MIBG scintigraphy for the diagnosis of PCT.
Adrenocortical masses are among the most common tumors in humans. However, only a small proportion of these tumors cause endocrine diseases (such as primary hyperaldosteronism, hypercortisolism, hyperandrogenism, or hyperestrogenism), and less than 1% are malignant. In recent years, several of the molecular and cellular mechanisms involved in adrenal tumorigenesis have been unraveled. As a result, alterations in intercellular communication, local production of growth factors and cytokines, and aberrant expression of ectopic receptors on adrenal tumor cells have been implicated in adrenal cell growth, hyperplasia, tumor formation, and autonomous hormone production. Genetic and chromosomal abnormalities, including several chromosomal loci and the genes coding for p53, p57, and insulin-like growth factor II, have been reported in adrenal tumors. In addition, chromosomal markers have been identified in several familial syndromes associated with adrenal tumors; these include menin, which is responsible for multiple endocrine neoplasia type I, and the hybrid gene that causes glucocorticoid-remediable hyperaldosteronism. Algorithms for endocrine testing and imaging procedures are now available to codify screening for, confirmation of, and differentiation of causes of primary hyperaldosteronism and the Cushing syndrome. Improved radiologic, computerized radiologic, and magnetic resonance imaging techniques, as well as selective catheterization studies, are useful in localizing adrenal tumors and in distinguishing between benign and malignant lesions and between functional and nonfunctional nodules. Finally, recent refinements in the field of minimally invasive general surgery have made laparoscopic adrenalectomy the method of choice for removing adrenal tumors; this type of surgery allows shorter hospital stays, lower morbidity rates, and faster recovery.
Both pheochromocytomas and neuroblastomas can now be identified and located with a high level of accuracy. Scintigraphy with MIBG has become an indispensable diagnostic method for defining the extent and location of many if not most pheochromocytomas. To define the stage, to document the course and to evaluate the response to therapies in patients with neuroblastoma, imaging with MIBG is now essential.
Selecting the appropriate approach for resection and follow-up of pheochromocytomas (PCCs) is highly dependent upon reliable localization and exclusion of multifocal, bilateral, or metastatic disease. Metaiodobenzylguanidine (MIBG) scintigraphy was developed for functional localization of catecholamine-secreting tissues. Somatostatin receptor imaging (SRI) has a high sensitivity for localizing head and neck paragangliomas, but studies of intraabdominal PCCs are rare. In this study we review our experience of [(123)I]MIBG and SRI, performed since 1983 and 1989, respectively, in the work-up of primary and recurrent PCCs. Scintigraphic results were correlated with catecholamine secretion, size and site, malignancy, associated tumor syndromes, and morphological features. [(123)I]MIBG scans were performed in a total of 75 patients, in 70 cases before resection of primary PCCs and in 5 cases because of recurrent disease. Ninety-one PCCs were resected. The overall detection rates were 83.3% and 89.8% for PCCs larger than 1.0 cm. Multifocal disease was detected in 4 patients with [(123)I]MIBG. [(123)I]MIBG uptake correlated with greater size of PCC (r = 0.33; P = 0.008) and greater concentration of plasma epinephrine (r = 0.32; P = 0.006). [(123)I]MIBG-negative PCCs (n = 14) had significantly (P = 0.01) smaller diameters than [(123I)]MIBG-positive tumors. Furthermore, [(123)I]MIBG uptake was significantly higher in unilateral (P = 0.02), benign (P = 0.02), sporadic (P = 0.02), intraadrenal (P = 0.02), and capsular invasive (P = 0.03) PCCs than in bilateral, malignant, MEN2A/2B-related, extraadrenal, and noninvasive PCCs, respectively. The detection rate of SRI was only 25% (8 of 32) for primary benign PCCs. In 14 patients metastases occurred, which were effectively visualized with [(123)I]MIBG in 8 of 14 cases. SRI was able to detect metastases in 7 of 8 cases, including 3 [(123)I]MIBG-negative metastatic cases. In addition, [(123)I]MIBG and SRI detected 2 recurrences. In conclusion, [(123)I]MIBG uptake is correlated with the size, epinephrine production, and site of PCCs. Its role in bilateral and MEN2A/2B-related PCCs seems limited. In cases of recurrent elevation of catecholamines, localization of metastases and/or recurrence should be attempted with [(123)I]MIBG scintigraphy. In suspicious metastatic PCCs, SRI might be considered to supplement [(123)I]MIBG scintigraphy.
The diagnosis and treatment of pheochromocytoma depend critically on effective means to localize the tumor. Computed tomography and magnetic resonance imaging have good sensitivity but poor specificity for detecting pheochromocytoma, and nuclear imaging approaches such as (131)I-metaiodobenzylguanidine scintigraphy have limited sensitivity. Here we report initial results using 6-[(18)F]fluorodopamine positron emission tomography (PET) scanning in the diagnostic localization of pheochromocytoma. Twenty-eight patients with known or clinically suspected pheochromocytoma underwent PET scanning after intravenous injection of 6-[(18)F]fluorodopamine. Of the 28 patients, 9 had surgical confirmation of the tumor, 8 had previously diagnosed metastatic pheochromocytoma, and 11 had plasma levels of metanephrines that were within normal limits. All 9 patients with surgically proven pheochromocytoma had abnormal 6-[(18)F]fluorodopamine PET scans that identified the tumors. All 8 patients with metastatic pheochromocytoma had extra-adrenal sites of 6-[(18)F]fluorodopamine-derived activity. Of the 11 patients with normal plasma levels of metanephrines, 9 had negative 6-[(18)F]fluorodopamine PET scans, 1 had extra-adrenal foci of 6-[(18)F]fluorodopamine-derived activity, and 1 had symmetric uptake of 6-[(18)F]fluorodopamine in the region of the adrenal glands. In patients with known disease, 6-[(18)F]fluorodopamine PET scanning can detect and localize pheochromocytomas with high sensitivity. In patients in whom the diagnosis of pheochromocytoma is considered but excluded because of negative plasma metanephrine results, 6-[(18)F]fluorodopamine PET scans are consistently negative. These findings justify a clinical trial of 6-[(18)F]fluorodopamine PET scanning as a diagnostic tool.
Catecholamines are translocated across plasma membranes by transporters that belong to two large families with mainly neuronal or extraneuronal locations. In mammals, neuronal uptake of catecholamines involves the dopamine transporter (DAT) at dopaminergic neurons and the norepinephrine transporter (NET) at noradrenergic neurons. Extraneuronal uptake of catecholamines is mediated by organic cation transporters (OCTs), including the classic corticosterone-sensitive extraneuronal monoamine transporter. Catecholamine transporters function as part of uptake and metabolizing systems primarily responsible for inactivation of transmitter released by neurons. Additionally, the neuronal catecholamine transporters, recycle catecholamines for rerelease, thereby reducing requirements for transmitter synthesis. In a broader sense, catecholamine transporters function as part of integrated systems where catecholamine synthesis, release, uptake, and metabolism are regulated in a coordinated fashion in response to the demands placed on the system. Location is also important to function. Neuronal transporters are essential for rapid termination of the signal in neuronal-effector organ transmission, whereas non-neuronal transporters are more important for limiting the spread of the signal and for clearance of catecholamines from the bloodstream. Besides their presynaptic locations, NET and DAT are also present at several extraneuronal locations, including syncytiotrophoblasts of the placenta and endothelial cells of the lung (NET), stomach and pancreas (DAT). The extraneuronal monoamine transporter shows a broad tissue distribution, whereas the other two non-neuronal catecholamine transporters (OCT1 and OCT2) are mainly localized to the liver, kidney, and intestine. Altered function of peripheral catecholamine transporters may be involved in disturbances of the autonomic nervous system, such as occurs in congestive heart failure and hypernoradrenergic hypertension. Peripheral catecholamine transporters provide important targets for clinical imaging of sympathetic nerves and diagnostic localization and treatment of neuroendocrine tumors, such as neuroblastomas and pheochromocytomas.
To evaluate fluorine 18 ((18)F) dihydroxyphenylalanine (DOPA) whole-body positron emission tomography (PET) as a biochemical imaging approach for detection of pheochromocytomas.
(18)F DOPA PET and magnetic resonance (MR) imaging were performed in 14 consecutive patients suspected of having pheochromocytomas (five sporadic, nine with von Hippel-Lindau disease); metaiodobenzylguanidine (MIBG) scintigraphy was performed in 12 of these patients. The individual imaging findings were assessed in consensus by specialists in nuclear medicine and radiologists blinded to the results of the other methods. The findings of the functional imaging methods were compared with those of MR imaging, the reference standard. Histologic verification could be obtained in eight patients with nine tumors.
Seventeen pheochromocytomas (11 solitary, three bifocal; 14 adrenal, three extraadrenal) were detected with MR imaging. (18)F DOPA PET and MR imaging had concordant results in all 17 tumors. In contrast, MIBG scintigraphy had false-negative results in four patients with three adrenal tumors smaller than 2 cm and one extraadrenal tumor with a diameter of 3.6 cm. On the basis of these data, sensitivities of 100% for (18)F DOPA PET and of 71% for MIBG scintigraphy were calculated. Specificity was 100% for both procedures.
(18)F DOPA PET is highly sensitive and specific for detection of pheochromocytomas and has potential as the functional imaging method of the future.
This review provides current understanding of the pathophysiology of pheochromocytoma and the wide range of associated clinical manifestations that have led to earlier recognition of the disease. In addition, it reviews optimal screening methods and localization techniques that have enhanced the clinician’s ability to make the diagnosis with greater certainty. This article will also discuss alternative antihypertensive regimens and innovative anesthetic and surgical procedures that have made successful management more promising than ever before.
Areas requiring further development include additional clinical experience with the measurement of plasma metanephrines that have been shown to have high sensitivity and specificity in the diagnosis of sporadic and familial pheochromocytoma, optimizing cost effectiveness of diagnostic imaging, improving the ability to predict and treat malignant pheochromocytoma, and elucidating not only the surgical approach but, perhaps with rapid advances in molecular genetics, ways of preventing familial pheochromocytoma.
Pheochromocytomas and paragangliomas are tumors of the autonomic nervous system; pheochromocytomas are tumors of the adrenal medulla, and paragangliomas are extra-adrenal tumors arising from either the sympathetic nervous system or parasympathetic ganglia. It has previously been estimated that approximately 10%-15% of pheochromocytomas are due to hereditary causes. However, our increased understanding of the three hereditary syndromes (neurofibromatosis 1, multiple endocrine neoplasia type 2, and von Hippel-Lindau syndrome) in which pheochromocytoma is found and the recent discovery that mutations in genes in the succinate dehydrogenase family (SDHB and SDHD) predispose to pheochromocytoma have necessitated a re-evaluation of the genetic basis of pheochromocytoma. These studies indicate that the frequency of germline mutations associated with isolated pheochromocytoma is higher than previously estimated, with both hospital-based series and a large population-based series indicating that the frequency of germline mutations in RET, VHL, SDHB, and SDHD taken together approximates 20%. In all patients with pheochromocytoma, including those with known hereditary syndrome or a positive family history, the frequency of germline mutations in these four genes together approaches 30%. Given the frequency of germline mutations, consideration should be given to genetic counseling for all patients with pheochromocytoma and is particularly important for individuals with a positive family history, multifocal disease, or a diagnosis before age 50. Identification of patients with hereditary pheochromocytoma is important because it can guide medical management in mutation-positive patients and their families. This review provides an overview of the known genetic syndromes that are commonly associated with pheochromocytoma, examines recent data on the association of germline mutations in the succinate dehydrogenase gene family with pheochromocytoma, and suggests guidelines for the genetic evaluation of pheochromocytoma patients.
Iodine 123 meta-iodobenzylguanidine (MIBG) scintigraphy has been used in patients with clinical suspicion of pheochromocytoma to confirm the nature of an adrenal or extraadrenal mass or to identify occult disease. Additionally, it may be used to identify unsuspected bilaterality or metastases in the setting of a known unilateral adrenal mass before operation. We sought to determine the role of (123)I MIBG scintigraphy in this apparently routine preoperative setting. Our hypothesis was that (123)I MIBG would provide additional preoperative information that could modify operative intervention.
All patients undergoing (123)I MIBG scintigraphy at our institution between 1992 and 2002 were identified. MIBG results, operative procedures and findings, and pathologic findings were retrospectively reviewed and compared.
The (123)I MIBG scintigraphy was performed in a total of 315 patients. Of these, 48 were patients with an initial biochemical diagnosis of pheochromocytoma and a unilateral adrenal mass. 47 of the 48 (98%) primary scans were positive for a single focus of activity concordant with anatomic imaging data from computed tomography or magnetic resonance imaging and operative findings. The (123)I MIBG did not reveal unsuspected metastatic or bilateral disease in any patient.
In this large series of patients undergoing (123)I MIBG scintigraphy, the test served only to confirm diagnostic impressions and corroborate anatomic imaging. The (123)I MIBG did not alter the operative management of any patient with a solitary adrenal lesion in the clinical context of biochemically-proven catecholamine excess.
To evaluate the accuracy of carbon 11 (11C) hydroxyephedrine (HED) positron emission tomography (PET) in the detection of pheochromocytomas.
Nineteen patients (12 women, seven men; mean age, 53 years) suspected of having pheochromocytoma were evaluated. Patients had enlarged adrenal glands at computed tomography and either increased urinary catecholamine levels (n = 18) or normal biochemistry (n = 1). Dynamic PET examination in the adrenal region was performed after injection of 800 MBq 11C HED. PET data were analyzed visually and semiquantitatively. Time-activity curves were generated for different organs. PET results were validated with histologic evaluation (n = 16) or clinical follow-up (n = 3). The diagnostic value of HED PET was evaluated by calculating the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy.
In 12 patients, 13 pheochromocytomas were verified at surgery and histologic evaluation. All but one of the pheochromocytomas were detected with HED PET, which demonstrated elevated uptake. The rest of the patients (n = 7) did not have pheochromocytomas. In these patients, HED PET did not show any abnormal uptake in the suspicious tumors (confirmed at surgery in four patients and at clinical follow-up in three). Mean standardized uptake value of the tumors was 21.4 (range, 11.1-40.9). The time-activity curves for pheochromocytomas showed early uptake after injection, and the activity increased with the time of examination. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of HED PET in the detection of pheochromocytomas were 92% (12 of 13), 100% (seven of seven), 100% (12 of 12), 87.5% (seven of eight), and 95% (19 of 20), respectively.
HED PET is useful in the detection of pheochromocytomas, providing a high level of accuracy.
To assess the impact of [(131)I]meta-iodobenzylguanidine ((131)MIBG) scintigraphy on the management of phaeochromocytoma.
Between 1982 and 2002, 83 patients with histologically proven phaeochromocytoma or paraganglioma were investigated using (131)MIBG scintigraphy. Seventeen of these patients, with a hereditary form of the disease, presented with 23 phaeochromocytomas [three neurofibromatosis type 1 (NF1), five von Hippel-Lindau disease (VHL), eight multiple endocrine neoplasia type 2A (MEN2A) and one type 2B (MEN2B)].
MIBG uptake was observed in 44/54 sporadic phaeochromocytomas (sensitivity 81.5%), 14/23 familial phaeochromocytomas (60.9%), 3/6 paragangliomas and 4/6 malignant phaeochromocytomas. No significant correlations were found between the degree of tracer uptake, tumour size and urinary metanephrine levels. No patients undergoing surgery for sporadic phaeochromocytoma had a second tumour located. Nine of 54 sporadic phaeochromocytomas had normal or mildly elevated urinary metanephrine levels (< 1.5 greater than normal). In eight of these patients, (131)MIBG was positive and confirmed the diagnosis of phaeochromocytoma. In malignant phaeochromocytomas (n = 6), MIBG demonstrated additional lesions not detected with computed tomography (CT) and/or magnetic resonance imaging (MRI) in three cases. The MIBG findings in the group with apparently sporadic paragangliomas (n = 6) were negative in four cases and failed to detect a cervical lesion in one multifocal paraganglioma.
(131)MIBG was useful in confirming the diagnosis in phaeochromocytomas with low levels of catecholamine secretion. It contributed little to the management of patients when used as a means of screening for multifocality in sporadic phaeochromocytoma, or the management of patients with familial phaeochromocytoma. However, MIBG can be an informative method of investigation when dealing with malignant/ectopic forms, although the sensitivity of MIBG is lower in this group of patients.
Clinically silent adrenal masses are discovered incidentally during diagnostic testing or treatment for clinical conditions that are not related to suspicion of adrenal disease; thus, they are commonly referred to as 'incidentalomas'. The widespread use of high-resolution anatomic imaging techniques such as computed tomography (CT) and magnetic resonance (MR) imaging has led to the increased detection of these masses. In many patients without a known extra-adrenal primary malignancy--and even in patients with a primary neoplasm--most adrenal masses ultimately prove to be benign. However, it remains important that these adrenal masses are accurately characterized to exclude the treatable causes of adrenal disease, and also to accurately stage the oncology patient. The purpose of this chapter is to describe the findings and recent advances in non-invasive imaging methods that are now available for the accurate characterization of incidentally detected adrenal masses (i.e. the differentiation of benign from malignant masses). The imaging techniques and the algorithms that are used in our institution for the evaluation of incidentally detected adrenal mass will be described.
Although the majority of pheochromocytomas (PHEO) are benign, a subset is malignant. Computed tomography (CT) and magnetic resonance imaging (MRI) localize PHEO with high sensitivity but, because of limited specificity, [(131)I]- or [(123)I]-metaiodobenzylguanidine ([(131)I]- or [(123)I]-MIBG) is often used as a complementary agent. 6-[18F]-fluorodopamine ([18F]-DA) has been developed as a radiopharmaceutical for the targeting of noradrenergic pathways, and has been shown to result in a better detection rate of PHEO sites than MIBG; however, [18F]-DA has shown a lack of accumulation in some patients with metastatic PHEO.
Five patients with widespread metastatic PHEO who had CT and MRI evidence of metastatic disease (one man and four women; age range, 25-64 years), and who underwent imaging with [(123)I]-MIBG, [18F]-DA and 2-[18F]-fluoro-2-deoxy-D-glucose ([18F]-FDG), were evaluated retrospectively. Tomographic imaging was performed and positron emission tomography (PET) images were inspected visually and quantitatively.
All five patients had [(123)I]-MIBG scans that grossly underestimated the extent of disease when compared with conventional CT and MRI. All lesions seen on [(123)I]-MIBG scans were detected on [18F]-DA scans, which also detected additional lesions. Nonetheless, [18F]-DA also failed to detect numerous lesions seen on CT and MRI. In all of these cases, [18F]-FDG PET showed lesions that were not detected on either [(123)I]-MIBG or [18F]-DA scans.
When [(123)I]-MIBG or [18F]-DA fails to localize lesions seen on conventional imaging studies, [18F]-FDG may be recommended as an ancillary test for the diagnosis and localization of metastatic PHEO. This is particularly important in patients with aggressive PHEO.
Pheochromocytomas are rare tumors of chromaffin cells for which the optimal management is surgical resection. Precise diagnosis and localization may be elusive. We evaluated whether positron emission tomography (PET) scanning with the combination of [18F]fluorodeoxyglucose (FDG) and the norepinephrine analogue [11C]metahydroxyephedrine (mHED) would allow more exact diagnosis and localization.
Fourteen patients with suspected pheochromocytoma were evaluated by anatomical imaging (computed tomography or magnetic resonance imaging) and [131I]metaiodobenzylguanidine (MIBG) planar imaging. PET imaging was performed by using mHED with dynamic adrenal imaging, followed by a torso survey and FDG with a torso survey. Images were evaluated qualitatively by an experienced observer.
Eight patients had pathology-confirmed pheochromocytoma. Of the other six, two patients had normal adrenal tissue at adrenalectomy, and the other four had subsequent clinical courses inconsistent with a diagnosis of pheochromocytoma. In four of eight patients with pheochromocytoma, MIBG failed to detect one or more sites of pathology-confirmed disease. The mHED-PET detected all sites of confirmed disease, whereas FDG-PET detected all sites of adrenal and abdominal disease, but not bone metastases, in one patient. MIBG and FDG-PET results were all negative in the six patients without pheochromocytoma. One patient with adrenal medullary hyperplasia had a positive mHED-PET scan. PET scanning aided the decision not to operate in three of six patients. The resolution of PET functional imaging was superior to that of MIBG.
PET scanning for pheochromocytoma offers improved quality and resolution over current diagnostic approaches. PET may significantly influence the clinical management of patients with a suspicion of these tumors and warrants further investigation.
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