Advances in the diagnostic imaging of pheochromocytomas

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 18 F-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.

Related papers:

title: Malignant Pheochromocytoma
abstract: The prevalence of malignant pheochromocytoma is about 10%, and is somewhat higher for paraganglioma. A problem for clinical follow‐up is that patients with “benign” histopathologic findings may develop metastatic disease. At the first international symposium on pheochromocytoma in Bethesda (2005) experts from different disciplines and patients shared their experiences, and the present knowledge of this rare disease was updated. The discussion related to future strategies for better clinical/histopathologic diagnosis and understanding of different geno‐ and phenotypes. Curative surgery can only seldom be performed because of multiple metastases. The main therapeutic goal is therefore often tumor reduction and control of hypertension. To date the best adjunct to surgery is radionuclide therapy using 131I‐MIBG, but the background information for optimal treatment is still incomplete. Certain patients may benefit from 131I‐MIBG combined with radiotherapy via somatostatin receptors expressed by the tumor, or the combination with chemotherapy. The need for future multicenter studies was emphasized. In experimental models the work on enhanced expression of amine transporters critical for radiotherapy is continued. Ongoing microarray studies will reveal novel intracellular pathways of importance for proliferation/cell cycle control, which can be inhibited by pharmacologic tools.

title: Use of 131I-MIBG scintigraphy in the evaluation of suspected pheochromocytoma.
abstract: Studies at the University of Michigan have shown that 131I-metaiodobenzylguanidine (131I-MIBG) is an effective agent for the diagnosis and localization of pheochromocytomas and paragangliomas. We conducted a study that confirmed and expanded that finding. From January 1983 to March 1984, 48 patients at our institution had 51 131I-MIBG scans during the workup of suspected sporadic or metastatic pheochromocytoma. Scintigrams were obtained after 500 microCI of 131I-MIBG had been administered intravenously. The final diagnosis (true-positive, false-negative, or false-positive result) was made at operation and pathologic examination. A true-negative diagnosis was confirmed by normal plasma and fractionated urinary levels of catecholamines and metabolites and, in most patients, computed tomography (CT). There were 20 true-positive studies (6 pheochromocytomas, 4 paragangliomas, and 10 metastatic or recurrent pheochromocytomas) and 24 true-negative studies. One patient with a suspected recurrent paraganglioma near the bladder had a false-positive 131I-MIBG scan (and also a false-positive (CT). Among six patients with false-negative scintigrams (three pheochromocytomas, one paraganglioma, and two metastatic lesions), one also had a false-negative CT. The overall sensitivity of 131I-MIBG scanning was 77%, specificity was 96%, and accuracy was 86%. This test is fairly sensitive in the workup of patients with known or suspected recurrent or metastatic pheochromocytoma. It may also be helpful in the evaluation of suspected sporadic pheochromocytoma when CT findings are normal.

title: Aspects on Radionuclide Therapy in Malignant Pheochromocytomas
abstract: Malignant pheochromocytomas/paragangliomas (PCs/PGs) often have distant metastases to the skeleton, liver, and lungs. Radionuclide therapy is valuable for treatment of disseminated tumor disease and could be used as adjuvant therapy after surgery. Patients with local and/or distant metastases of PC/PG should be investigated preoperatively by scintigraphy using both 123I‐MIBG and 111In‐DTPA‐D‐Phe1‐octreotide, to evaluate the possibilities for radionuclide therapy (i.e., a dosimetric estimation of radiation dose to the tumor tissue versus critical normal tissues). Individual patient dose‐planning should be performed. For patients in whom positive therapeutic effects are anticipated radionuclide therapy can be applied. Therapy with both 131I‐MIBG and 177Lu‐octreotate might be favorable in individual patients with lesions visualized by both metaiodobenzylguanidine (MIBG) and octreotide scintigraphy with enhanced therapeutic effects and reduced side effects.

title: Malignant Pheochromocytoma in a Population‐Based Study
abstract: One hundred fifty‐four consecutive patients with pheochromocytoma (PC, n= 137) or paraganglioma (PG, n= 17) were treated at our unit. Twenty patients had MEN 2, 15 VRD, and 1 VHL tumors. Twelve had malignant tumors and were classified according to mode of presentation: (1) Distant metastases (n= 4); three underwent surgical debulking (with chemotherapy in one); and three had 131I‐MIBG therapy. Within 4 years two patients died of tumor progression. (2) Locally advanced disease (n= 4), all resected for cure. (3) Malignancy disclosed during follow‐up after adrenalectomy with “benign” histopathology (n= 4). All patients in groups 2 and 3 developed recurrence 9 (1–17) years after primary surgery; four underwent resection, one remains tumor‐free. The others were treated chronically with phenoxybenzamine, combined with 131I‐MIBG in one. These eight patients were observed 20 (5–35) years after primary surgery and 11 (1–19) years after recurrence. This series is population‐based and may better reflect the natural history of malignant PC/PG than the series from national referral centers. Active surgical treatment and phenoxybenzamine resulted in low tumor‐related mortality in groups 2 and 3; five patients died 8–30 years after diagnosis, four of PC/PG (three from group 2 and one from group 3 ) and one of other causes. We propose tumor uptake studies (MIBG‐ and octreotide scintigraphy) in patients with nonresectable metastases; to select individual radionuclide therapy data on the expression of CA‐transporters/somatostatin receptors may be helpful. To diagnose PC/PG early, screening of adrenal incidentalomas has been suggested. In a regional population‐based prospective study, 503 incidentalomas were reported during 18 months, but only one patient with PG was identified.

title: Distinct pharmacological properties and distribution in neurons and endocrine cells of two isoforms of the human vesicular monoamine transporter.
abstract: A second isoform of the human vesicular monoamine transporter (hVMAT) has been cloned from a pheochromocytoma cDNA library. The contribution of the two transporter isoforms to monoamine storage in human neuroendocrine tissues was examined with isoform-specific polyclonal antibodies against hVMAT1 and hVMAT2. Central, peripheral, and enteric neurons express only VMAT2. VMAT1 is expressed exclusively in neuroendocrine, including chromaffin and enterochromaffin, cells. VMAT1 and VMAT2 are coexpressed in all chromaffin cells of the adrenal medulla. VMAT2 alone is expressed in histamine-storing enterochromaffin-like cells of the oxyntic mucosa of the stomach. The transport characteristics and pharmacology of each VMAT isoform have been directly compared after expression in digitonin-permeabilized fibroblastic (CV-1) cells, providing information about substrate feature recognition by each transporter and the role of vesicular monoamine storage in the mechanism of action of psychopharmacologic and neurotoxic agents in human. Serotonin has a similar affinity for both transporters. Catecholamines exhibit a 3-fold higher affinity, and histamine exhibits a 30-fold higher affinity, for VMAT2. Reserpine and ketanserin are slightly more potent inhibitors of VMAT2-mediated transport than of VMAT1-mediated transport, whereas tetrabenazine binds to and inhibits only VMAT2. N-methyl-4-phenylpyridinium, phenylethylamine, amphetamine, and methylenedioxymethamphetamine are all more potent inhibitors of VMAT2 than of VMAT1, whereas fenfluramine is a more potent inhibitor of VMAT1-mediated monamine transport than of VMAT2-mediated monoamine transport. The unique distributions of hVMAT1 and hVMAT2 provide new markers for multiple neuroendocrine lineages, and examination of their transport properties provides mechanistic insights into the pharmacology and physiology of amine storage in cardiovascular, endocrine, and central nervous system function.

title: Current Trends in Functional Imaging of Pheochromocytomas and Paragangliomas
abstract: Most pheochromocytomas/paragangliomas should be evaluated with anatomical imaging (computed tomography or magnetic resonance imaging) followed by functional imaging (nuclear medicine modalities). Functional imaging assures that the tumor is indeed a pheochromocytoma/paraganglioma and enables more thorough localization, especially detecting as many lesions as possible (in particular for metastatic disease). Functional imaging for pheochromocytomas/paragangliomas, can use radiolabled ligands specific for pathways of synthesis, metabolism, and inactivation of catecholamines or nonspecific ligands. In an overview of the available nuclear medicine modalities, we summarize the accumulated experience and recommend when functional imaging should be applied to patients with pheochromocytoma/paraganglioma.

title: Biochemical diagnosis of pheochromocytoma: which test is best?
abstract: Diagnosis of pheochromocytoma depends on biochemical evidence of catecholamine production by the tumor. However, the best test to establish the diagnosis has not been determined.



To determine the biochemical test or combination of tests that provides the best method for diagnosis of pheochromocytoma.



Multicenter cohort study of patients tested for pheochromocytoma at 4 referral centers between 1994 and 2001. The analysis included 214 patients in whom the diagnosis of pheochromocytoma was confirmed and 644 patients who were determined to not have the tumor.



Test sensitivity and specificity, receiver operating characteristic curves, and positive and negative predictive values at different pretest prevalences using plasma free metanephrines, plasma catecholamines, urinary catecholamines, urinary total and fractionated metanephrines, and urinary vanillylmandelic acid.



Sensitivities of plasma free metanephrines (99% [95% confidence interval [CI], 96%-100%]) and urinary fractionated metanephrines (97% [95% CI, 92%-99%]) were higher than those for plasma catecholamines (84% [95% CI, 78%-89%]), urinary catecholamines (86% [95% CI, 80%-91%]), urinary total metanephrines (77% [95% CI, 68%-85%]), and urinary vanillylmandelic acid (64% [95% CI, 55%-71%]). Specificity was highest for urinary vanillylmandelic acid (95% [95% CI, 93%-97%]) and urinary total metanephrines (93% [95% CI, 89%-97%]); intermediate for plasma free metanephrines (89% [95% CI, 87%-92%]), urinary catecholamines (88% [95% CI, 85%-91%]), and plasma catecholamines (81% [95% CI, 78%-84%]); and lowest for urinary fractionated metanephrines (69% [95% CI, 64%-72%]). Sensitivity and specificity values at different upper reference limits were highest for plasma free metanephrines using receiver operating characteristic curves. Combining different tests did not improve the diagnostic yield beyond that of a single test of plasma free metanephrines.



Plasma free metanephrines provide the best test for excluding or confirming pheochromocytoma and should be the test of first choice for diagnosis of the tumor.

title: Phaeochromocytomas presenting as acute crises after beta blockade therapy
abstract: Objective   Phaeochromocytoma crisis is a life‐threatening emergency that may be undiagnosed because of its numerous, nonspecific manifestations. We analysed, retrospectively, the presentation, management and outcome of patients who were admitted to our institution with phaeochromocytoma crises over a 5‐year period.

title: Pheochromocytoma: an update on genetics and management.
abstract: Pheochromocytomas (PHEOs) are rare neoplasms that produce catecholamines and usually arise from the adrenal medulla and are considered to be an adrenal paraganglioma (PGL). Closely related tumors of extraadrenal sympathetic and parasympathetic paraganglia are classified as extraadrenal PGLs. Most PHEOs are sporadic, but a significant percentage (approximately 25%) may be found in patients with germline mutations of genes predisposing to the development of von Hippel-Lindau disease, neurofibromatosis 1, multiple endocrine neoplasia type 1 (MEN1) and 2 (MEN2), and the PGL/PHEOs syndrome, based on the described mutations of the genes for succinate dehydrogenase subunit D (SDHD), B (SDHB), and C (SDHC). As one out of four PHEOs turns out to be a hereditary clinical entity, screening for genetic alterations is important, as it provides useful information for a rational diagnostic approach and management. This review discusses the genetics, the pathophysiology of hypertension, the clinical picture, the biochemical and imaging diagnosis, and the preferred therapeutic approach for PGLs/PHEOs. Furthermore, it emphasizes the need for genetic testing in cases with apparently sporadic PHEOs.

title: Pheochromocytoma and functional paraganglioma syndrome: No longer the 10% tumor
abstract: Pheochromocytomas and abdominal paragangliomas are catecholamine‐producing tumors of the sympathetic nervous system, while head and neck paragangliomas are non‐secreting tumors of parasympathetic origin. Recent developments in clinical and molecular research on these tumor forms have significantly clarified their genetic backgrounds and challenged the view of “pheochromocytoma as the 10% rule tumor.” Firstly, a larger proportion of these tumors are today discovered in normotensive patients during imaging carried out for other reasons than suspicion of pheochromocytoma. Secondly, although the differential diagnosis between malignant and benign tumors remains a challenge, the risk of malignancy well exceeds the classical 10% in patients with extra‐adrenal disease, and/or carriers of germ‐line SDHB mutations. Finally, up to a third of patients carry a germ‐line mutation in a gene predisposing to pheochromocytoma and/or paraganglioma. Identification of a constitutional mutation in RET, VHL, SDHD, or SDHB has implications for clinical screening and follow‐up for both the patient and for relatives at risk who can be identified by screening for the same mutation. Genetic testing in apparently sporadic cases is therefore regarded as beneficial, especially in patients diagnosed before 50 years of age, and in patients with bilateral, multifocal, malignant and/or extra‐adrenal disease.

title: Genetics and biology of pheochromocytoma.
abstract: The familial forms of pheochromocytoma have recently been demonstrated to be more frequent than believed in the past. The genes currently known to be responsible for tumor formation are RET, VHL, NF1, SDHB, SDHC and SDHD. Germline mutations of these genes increase the risk of developing pheochromocytomas and/or paragangliomas which variably associate with other neoplasms and characterize diverse clinical syndromes such as MEN 2, von Hippel-Lindau (VHL), and neurofibromatosis type 1 (NF 1), or the PGL syndromes, respectively. Although the pathogenesis of pheochromocytoma/paraganglioma formation is still largely unknown, studies of the familial forms have started to uncover some pathways that favor tumor formation, such as activation of tyrosine-kinase, induction of hypoxia-inducible factors, activation of the oncogene Ras or reduced apoptosis. These studies have also demonstrated that various gene mutations can differently affect the biological characteristics of pheochromocytoma: for example, while the tumors are mostly adrenergic (epinephrine secreting) and episodically secreting in MEN 2, they are mostly noradrenergic (norepinephrine secreting) and continuously secreting in VHL. Biological variability can also be observed in the PGL syndromes where tumors develop in the head and neck and are parasympathetic in origin and non-secreting, or in the thorax and the abdomen, where they are sympathetic in origin and catecholamine secreting. Genetic testing in patients with pheochromocytomas or paragangliomas is, at present, strongly recommended and is mandatory in young patients or in cases of multiple or recurrent tumors. The clinical picture and the biological characteristics of the tumor may suggest the priority of the genes to be tested first.

title: Familial malignant catecholamine-secreting paraganglioma with prolonged survival associated with mutation in the succinate dehydrogenase B gene.
abstract: Approximately 10% of catecholamine-secreting tumors are malignant, and 10% are familial. These tumors have been associated with several hereditary syndromes, including multiple endocrine neoplasia type 2, von Hippel-Lindau syndrome, neurofibromatosis type 1, and familial paraganglioma. Mutations in succinate dehydrogenase (SDH) subunit genes have been identified in some kindreds with catecholamine-secreting tumors. In 1972 at the Mayo Clinic, a metastatic catecholamine-secreting paraganglioma was diagnosed in a 32-yr-old man. In 1979, 7 yr after the initial surgical treatment, a lytic metastasis to the left femur was found and was treated with local external radiotherapy. Locally metastatic abdominal catecholamine-secreting paragangliomas were diagnosed in the patient's 27-yr-old son. Analyses of the VHL, RET, SDHD, and SDHC genes revealed no mutations. However, a missense point mutation was detected in the SDHB gene: c.725G-->A in exon 7, which alters a conserved arginine at amino acid position 242 to a histidine (R242H). Sequencing of the SDHB gene in the tumors did not reveal any somatic mutations or loss of heterozygosity of the remaining allele. Thirty years after the initial diagnosis, the father is one of the longest living survivors of malignant catecholamine-secreting paraganglioma. Our findings indicate that mutations in SDHB may be associated with metastatic, yet clinically indolent, abdominal paraganglioma in some families.

title: Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma.
abstract: Hereditary paraganglioma (PGL) is characterized by the development of benign, vascularized tumors in the head and neck. The most common tumor site is the carotid body (CB), a chemoreceptive organ that senses oxygen levels in the blood. Analysis of families carrying the PGL1 gene, described here, revealed germ line mutations in the SDHD gene on chromosome 11q23. SDHD encodes a mitochondrial respiratory chain protein-the small subunit of cytochrome b in succinate-ubiquinone oxidoreductase (cybS). In contrast to expectations based on the inheritance pattern of PGL, the SDHD gene showed no evidence of imprinting. These findings indicate that mitochondria play an important role in the pathogenesis of certain tumors and that cybS plays a role in normal CB physiology.

title: SDH5 mutations and familial paraganglioma: somewhere Warburg is smiling.
abstract: Paragangliomas have been linked to mutations affecting the succinate dehydrogenase complex. In a recent issue of Science, Rutter and coworkers showed that SDH5 is required for the flavination of SDHA, which is necessary for SDH assembly and function. Moreover, they detected SDH5 mutations in a large kindred with familial paraganglioma.

title: Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma.
abstract: The pheochromocytomas are an important cause of secondary hypertension. Although pheochromocytoma susceptibility may be associated with germline mutations in the tumor-suppressor genes VHL and NF1 and in the proto-oncogene RET, the genetic basis for most cases of nonsyndromic familial pheochromocytoma is unknown. Recently, pheochromocytoma susceptibility has been associated with germline SDHD mutations. Germline SDHD mutations were originally described in hereditary paraganglioma, a dominantly inherited disorder characterized by vascular tumors in the head and the neck, most frequently at the carotid bifurcation. The gene products of two components of succinate dehydrogenase, SDHC and SDHD, anchor the gene products of two other components, SDHA and SDHB, which form the catalytic core, to the inner-mitochondrial membrane. Although mutations in SDHC and in SDHD may cause hereditary paraganglioma, germline SDHA mutations are associated with juvenile encephalopathy, and the phenotypic consequences of SDHB mutations have not been defined. To investigate the genetic causes of pheochromocytoma, we analyzed SDHB and SDHC, in familial and in sporadic cases. Inactivating SDHB mutations were detected in two of the five kindreds with familial pheochromocytoma, two of the three kindreds with pheochromocytoma and paraganglioma susceptibility, and 1 of the 24 cases of sporadic pheochromocytoma. These findings extend the link between mitochondrial dysfunction and tumorigenesis and suggest that germline SDHB mutations are an important cause of pheochromocytoma susceptibility.

title: UOK 262 cell line, fumarate hydratase deficient (FH-/FH-) hereditary leiomyomatosis renal cell carcinoma: in vitro and in vivo model of an aberrant energy metabolic pathway in human cancer.
abstract: Energy deregulation and abnormalities of tumor cell metabolism are critical issues in understanding cancer. Hereditary leiomyomatosis renal cell carcinoma (HLRCC) is an aggressive form of RCC characterized by germline mutation of the Krebs cycle enzyme fumarate hydratase (FH), and one known to be highly metastatic and unusually lethal. There is considerable utility in establishing preclinical cell and xenograft models for study of disorders of energy metabolism, as well as in development of new therapeutic approaches targeting of tricarboxylic acid (TCA) cycle enzyme-deficient human cancers. Here we describe a new immortalized cell line, UOK 262, derived from a patient having aggressive HLRCC-associated recurring kidney cancer. We investigated gene expression, chromosome profiles, efflux bioenergetic analysis, mitochondrial ultrastructure, FH catabolic activity, invasiveness, and optimal glucose requirements for in vitro growth. UOK 262 cells have an isochromosome 1q recurring chromosome abnormality, i(1)(q10), and exhibit compromised oxidative phosphorylation and in vitro dependence on anaerobic glycolysis consistent with the clinical manifestation of HLRCC. The cells also display glucose-dependent growth, an elevated rate of lactate efflux, and overexpression of the glucose transporter GLUT1 and of lactate dehydrogenase A (LDHA). Mutant FH protein was present primarily in edematous mitochondria, but with catalytic activity nearly undetectable. UOK 262 xenografts retain the characteristics of HLRCC histopathology. Our findings indicate that the severe compromise of oxidative phosphorylation and rapid glycolytic flux in UOK 262 are an essential feature of this TCA cycle enzyme-deficient form of kidney cancer. This tumor model is the embodiment of the Warburg effect. UOK 262 provides a unique in vitro and in vivo preclinical model for studying the bioenergetics of the Warburg effect in human cancer.

title: SDH5, a Gene Required for Flavination of Succinate Dehydrogenase, Is Mutated in Paraganglioma
abstract: Tapping the Mitochondrial Proteome Mitochondria produce the energy that cells need to survive, function, and divide. A growing list of human disorders has been traced to defects in mitochondrial function. About 300 mammalian mitochondrial proteins are functionally uncharacterized, and Hao et al. (p. 1139, published online 23 July) reasoned that the most highly conserved proteins within this group might provide insights into human disease. A combination of bioinformatics, yeast genetics, biochemistry, and human genetics was used to show that a previously uncharacterized mitochondrial protein (Sdh5) is required for the activity of respiratory complex II. Inactivating mutations in the human gene encoding SDH5 were found in individuals with hereditary paraganglioma, a rare neuroendocrine tumor. Thus, analysis of a mitochondrial protein in yeast has revealed a human tumor susceptibility gene. Analysis of a yeast mitochondrial protein reveals a human tumor susceptibility gene. Mammalian mitochondria contain about 1100 proteins, nearly 300 of which are uncharacterized. Given the well-established role of mitochondrial defects in human disease, functional characterization of these proteins may shed new light on disease mechanisms. Starting with yeast as a model system, we investigated an uncharacterized but highly conserved mitochondrial protein (named here Sdh5). Both yeast and human Sdh5 interact with the catalytic subunit of the succinate dehydrogenase (SDH) complex, a component of both the electron transport chain and the tricarboxylic acid cycle. Sdh5 is required for SDH-dependent respiration and for Sdh1 flavination (incorporation of the flavin adenine dinucleotide cofactor). Germline loss-of-function mutations in the human SDH5 gene, located on chromosome 11q13.1, segregate with disease in a family with hereditary paraganglioma, a neuroendocrine tumor previously linked to mutations in genes encoding SDH subunits. Thus, a mitochondrial proteomics analysis in yeast has led to the discovery of a human tumor susceptibility gene.

title: Warburg tumours and the mechanisms of mitochondrial tumour suppressor genes. Barking up the right tree?
abstract: The past decade has seen a revival of interest in the metabolic adaptations of tumours, named for their original discoverer, Otto Warburg. Warburg reported a high rate of glycolysis in tumours, and a concurrent defect in mitochondrial respiration. The rediscovery of Warburg's hypothesis coincided with the discovery of mitochondrial tumours suppressor genes that may conform to Warburg's hypothesis. Succinate dehydrogenase and fumarate hydratase are mitochondrial proteins of the TCA cycle and the respiratory chain and when mutated lead to tumours of the nervous system known as paragangliomas and pheochromocytomas, and in the case of fumarate hydratase, cutaneous and uterine leiomyomas and renal cell cancer. Recently a novel mitochondrial protein, SDHAF2 (SDH5), was also shown to be a paraganglioma-related tumour suppressor gene. Another mitochondrial and TCA cycle-related protein, isocitrate dehydrogenase 2 is, together with IDH1, frequently mutated in the brain tumour glioblastoma. There are currently many competing hypotheses on the role of these genes in tumourigenesis, but frequent themes are the stabilization of hypoxia inducible factor 1 and upregulation of genes involved in angiogenesis, glucose transport and glycolysis. Other postulated mechanisms include the inhibition of developmental apoptosis, altered gene expression due to histone deregulation and the acquisition of novel catalytic properties. Here we discuss these diverse hypotheses and highlight very recent findings on the possible effects of IDH gene mutations.

title: Genetic testing in pheochromocytoma or functional paraganglioma.
abstract: To assess the yield and the clinical value of systematic screening of susceptibility genes for patients with pheochromocytoma (pheo) or functional paraganglioma (pgl).



We studied 314 patients with a pheo or a functional pgl, including 56 patients having a family history and/or a syndromic presentation and 258 patients having an apparently sporadic presentation. Clinical data and blood samples were collected, and all five major pheo-pgl susceptibility genes (RET, VHL, SDHB, SDHD, and SDHC) were screened. Neurofibromatosis type 1 was diagnosed from phenotypic criteria.



We have identified 86 patients (27.4%) with a hereditary tumor. Among the 56 patients with a family/syndromic presentation, 13 have had neurofibromatosis type 1, and germline mutations on the VHL, RET, SDHD, and SDHB genes were present in 16, 15, nine, and three patients, respectively. Among the 258 patients with an apparently sporadic presentation, 30 (11.6%) had a germline mutation (18 patients on SDHB, nine patients on VHL, two patients on SDHD, and one patient on RET). Mutation carriers were younger and more frequently had bilateral or extra-adrenal tumors. In patients with an SDHB mutation, the tumors were larger, more frequently extra-adrenal, and malignant.



Genetic testing oriented by family/sporadic presentation should be proposed to all patients with pheo or functional pgl. We suggest an algorithm that would allow the confirmation of suspected inherited disease as well as the diagnosis of unexpected inherited disease.

title: High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing.
abstract: Adrenal and extraadrenal paragangliomas are tumors of chromaffin cells that are usually benign but that may also develop into malignant disease. Mutations of the gene for succinate dehydrogenase subunit B (SDHB) are associated with a high risk of malignancy, but establishing the precise contribution requires relatively large numbers of patients with well-defined malignancy.



We assessed the prevalence of SDHB mutations in a series of patients with malignant paraganglioma.



SDHB mutation testing was carried out in 44 consecutive patients with malignant paraganglioma. Clinical characteristics of patients with malignant disease due to SDHB mutations were compared with those without mutations.



Pathogenic SDHB mutations were found in 13 of the 44 patients (30%). Close to one third of patients had metastases originating from an adrenal primary tumor, compared with a little over two thirds from an extraadrenal tumor. Among the latter patients, the frequency of SDHB mutations was 48%.



This study establishes that missense, nonsense, frameshift, and splice site mutations of the SDHB gene are associated with about half of all malignancies originating from extraadrenal paragangliomas. The high frequency of SDHB germline mutations among patients with malignant disease, particularly when originating from an extraadrenal paraganglioma, may justify a high priority for SDHB germline mutation testing in these patients.

title: The optimal imaging of adrenal tumours: a comparison of different methods.
abstract: Computed tomography (CT; unenhanced, followed by contrast-enhanced examinations) is the cornerstone of imaging of adrenal tumours. Attenuation values of <10 Hounsfield units on an unenhanced CT are practically diagnostic for adenomas. When lesions cannot be characterised adequately with CT, magnetic resonance imaging (MRI) evaluation (with T1- and T2-weighted sequences and chemical shift and fat-suppression refinements) is sought. Functional nuclear medicine imaging is useful for adrenal lesions that are not adequately characterised with CT and MRI. Scintigraphy with [(131)I]-6-iodomethyl norcholesterol (a labelled cholesterol analogue) can differentiate adrenal cortical adenomas from carcinomas. Phaeochromocytomas appear as areas of abnormal and/or increased uptake of [(123)I]- and [(131)I]-meta-iodobenzylguanidine (a labelled noradrenaline analogue). The specific and useful roles of adrenal imaging include the characterisation of tumours, assessment of true tumour size, differentiation of adenomas from carcinomas and metastases, and differentiation of hyperfunctioning from non-functioning lesions. Adrenal imaging complements and assists the clinical and hormonal evaluation of adrenal tumours.

title: The incidental adrenal mass.
abstract: This article discusses the accuracy and complications of percutaneous biopsy of adrenal masses and the rapidly evolving new methods for noninvasive differential diagnosis using CT scan, MR imaging, and radio-nuclide scintigraphy. We offer our current recommendations for the evaluation of benign versus malignant adrenal masses and speculate on the optimal approach for the near future.

title: Radiolabeled adrenergi neuron-blocking agents: adrenomedullary imaging with [131I]iodobenzylguanidine.
abstract: The tissue distributions of three radioiodinated neuron-blocking agents have been determined in dogs. Iodine-125-labeled meta- and para-iodobenzylguanidines show a striking affinity for, and retention in, the adrenal medulla. Peak concentrations of the two isomers exceed those of previously reported adrenophilic compounds. High myocardial concentrations were also observed at early time intervals. Images of the dog's adrenal medullae have been obtained with para [131I]iodobenzylguanidine.

title: Myocardial imaging in man with I-123 meta-iodobenzylguanidine.
abstract: Meta-[123I]iodobenzylguanidine (m-[123I]IBG), a guanethidine analog, was used to image the myocardium in five normal male volunteers. Each subject received 2.0 mCi m-[123I]IBG intravenously. Four were given a bolus injection. Multiple myocardial scintigrams were obtained over a 2-hr period. Myocardial uptake was calculated by dividing the decay-corrected global myocardial count rate (after interpolated background correction) by the peak count rate during the first passage of the m-[123I]IBG bolus through the heart. The left ventricle could be visualized within 1-2 min of m-[123I]IBG injection. Mean myocardial uptake was 0.63% (range 0.45-0.78%) of injected dose at 5 min, and 0.76% (range 0.49-0.93%) at 2 hr (n = 4). m-[123I]IBG may provide quantitative information on myocardial catecholamine content.

title: Scintigraphic localization of pheochromocytoma.
abstract: We used a new radiopharmaceutical agent, [131I]meta-iodobenzylguanidine ([131I]MIBG), to produce scintigraphic images of pheochromocytomas in eight patients. One day or more after injection, the only normal organ that displayed distinct concentrations of radioactivity was the urinary bladder. The [131I]MIBG was probably concentrated in adrenergic vesicles; in tissues where vesicles are numerous, such as pheochromocytomas, the radionuclide was retained for days. The spectrum of pheochromocytomas shown the scintigrams was broad: intra-adrenal and extraadrenal in location, benign and malignant in character, 0.2 to 65 g in weight, and with different hormone patterns in secretion. Tumors in four patients were not detected by computed tomography. In one patient, reoperation was undertaken only because the scintigram located the extra-adrenal tumors and thereby directed the surgeon's exploration. The method offers hope of safe and reliable localization of pheochromocytomas in their many guises.

title: Radioisotope diagnosis and therapy of malignant pheochromocytoma
abstract: The availability of radiopharmaceuticals to depict primary malignant pheochromocytoma and its metastases has markedly changed the approach to these unusual cancers. Whole body screening afforded by scintigraphy allows remote tumor involvement to be identified and provides staging information necessary to guide subsequent therapy. The avid accumulation by malignant pheochromocytoma of some radiopharmaceuticals used for scanning has shown promise in therapeutic trials. In this paper, we discuss radiopharmaceuticals presently employed in malignant pheochromocytoma for both diagnostic and therapeutic uses and potential future compounds that may find their way into clinical practice in the approach to these and other related neoplasms.

title: Anatomical and Functional Imaging of Metastatic Pheochromocytoma
abstract: Although in the majority of patients with pheochromocytoma the tumor is localized in the adrenal, up to 26% of patients have malignant/metastatic disease. Metastatic disease should be ruled out before initial surgery is attempted. Anatomical imaging modalities (computed tomography or magnetic resonance imaging) should be done first over the adrenals, and if negative over the abdomen and if no tumor is found, then the chest and neck should be covered. Regardless of the anatomical imaging results functional imaging with [123‐I]‐ or [131‐I]‐metaiodobenzylguanidine (MIBG) scintigraphy should be done to corroborate the diagnosis. Negative MIBG scans should be followed by positron emission tomography (PET) studies with specific ligands like [18‐F]‐dopamine. Persistently negative evaluations should be followed by PET studies with non‐specific ligands such as [18‐F]‐deoxyglucose or somatostatin receptor scintigraphy.

title: Nuclear medicine imaging of pheochromocytoma and neuroblastoma.
abstract: 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.

title: Radiochemistry, biochemistry, and kinetics of 131I-metaiodobenzylguanidine (MIBG) and 123I-MIBG: clinical implications of the use of 123I-MIBG.
abstract: Metaiodobenzylguanidine (MIBG) is actively concentrated in adrenergic neuroendocrine tissues and tumors by an active, energy- and sodium-dependent, high-affinity, saturable mechanism. This has proved successful, when labeled with 131-I or 123-I, in scintigraphically depicting pheochromocytomas and neuroblastomas. For imaging purposes 123-I has multiple advantages over 131-I; the gamma ray energy is ideal for modern instruments, the decay by electron capture limits the particulate emissions, and the short half-life reduces the radiation burden. It is thus possible to use doses of 123-I-MIBG 20 times as large as doses of 131-I-MIBG with equivalent absorbed radiation doses. Disadvantages of 123-I include the cost and difficulties in the regular delivery of this short-lived radionuclide. For most imaging purposes 123-I-MIBG is the optimal agent if logistical problems in its supply can be overcome.

title: MR imaging and MIBG scintigraphy of pheochromocytomas and extraadrenal functioning paragangliomas.
abstract: To compare the potential of magnetic resonance (MR) imaging and scintigraphy performed with radiotracer-labeled metaiodobenzyl-guanidine (MIBG) in localization and characterization of functioning paragangliomas, the authors analyzed results of both modalities in 33 patients. Overall sensitivity for detection was 91% for MR imaging and 80% for MIBG scintigraphy. MR imaging demonstrated 100% of adrenal paragangliomas and 75% of extraadrenal paragangliomas, whereas MIBG scintigraphy revealed 75% and 88%, respectively. MIBG scintigraphy was more specific in the characterization of paragangliomas than MR imaging (100% vs 82%). However, MR imaging demonstrated nine other lesions not seen on scintigrams. On the basis of their results and other considerations, the authors believe MR imaging is the preferred initial technique when a functioning paraganglioma is suspected.

title: Can Quantification of VMAT and SSTR Expression Be Helpful for Planning Radionuclide Therapy of Malignant Pheochromocytomas?
abstract: Tumor‐specific uptake of the radio‐iodinated norepinephrine analogue meta‐iodobenzylguanidine (MIBG) or uptake of radiolabeled somatostatin analogues via somatostatin receptors (SSTRs) are possibilities to diagnose and treat malignant pheochromocytomas/paragangliomas (PCs/PGs) . The aims of this study were to investigate the quantitative expression of vesicular monoamine transporters (VMAT 1, 2) and all five SSTRs in malignant pheochromocytoma/paraganglioma (PC/PG) to evaluate the possibilities for tumor‐specific radionuclide therapy. High scintigraphic 123I‐MIBG uptake was found in two malignant PGs with high VMAT expression (500–730 copies of VMAT 1, 1,500–1,700 copies of VMAT 2 per 1,000 β‐actin), while no 123I‐MIBG uptake was found in the malignant PG with low VMAT expression (330 copies of VMAT 1, 350 copies of VMAT 2 per 1,000 β‐actin). The two patients with high VMAT expression and high 123I‐MIBG uptake were treated with 131I‐MIBG (2–3 × 8 GBq). In vitro, the VMAT antagonist, reserpine, and the membrane pump inhibitor, clomipramine, inhibited the uptake of 123I‐MIBG into tumor cells equally well (48% and 53% reduction respectively, P < 0.001). SSTR2 was the most abundant receptor subtype, but in the two malignant PGs its expression was only 110–260 copies/1,000 β‐actin. The transporters at the cell membrane and in the vesicular membrane both appear to be of importance for the uptake of 123I‐MIBG into malignant PC/PG. Quantitative determination of VMAT expression may be helpful in selecting patients suitable for radionuclide therapy with 131I‐MIBG. The present data indicate that SSTR‐mediated radionuclide therapy will not be effective treatment of malignant PC/PG.

title: Evaluation of meta-[211At]astatobenzylguanidine in an athymic mouse human neuroblastoma xenograft model.
abstract: A paired-label biodistribution was performed in athymic mice bearing SK-N-SH human neuroblastoma xenografts to compare the tissue uptake of meta-[211At]astatobenzylguanidine ([211At]MABG) and [131I]MIBG. Significantly higher (p < 0.05) uptake of [211At]MABG was seen in tumor (3.8 +/- 0.8% ID/g vs. 3.1 +/- 0.7% ID/g at 8 h) compared to [131I]MIBG. Desipramine reduced tumor uptake of [211At] MABG by 43%, suggesting that its accumulation was related to the specific uptake-1 mechanism. Higher uptake of [211At]MABG was also seen in normal tissue targets such as heart (6.0 +/- 0.9% ID/g vs. 4.5 +/- 0.8% ID/g at 8 h; p < 0.05). Pretreatment of mice with unlabeled MIBG increased tumor uptake of [211At]MABG by 1.5-fold while reducing uptake in heart and several other normal tissues. The vesicular uptake inhibitor tetrabenazine reduced heart uptake by 30% without reducing the tumor uptake. These results suggest such strategies might be useful for improving [211At]MABG tumor-to-normal tissue ratios.

title: Scintigraphic imaging of the adrenal glands.
abstract: This article presents the well established scintigraphic imaging techniques of the adrenal glands. Both adrenocortical scintigraphy with [131]6beta-iodomethylnorcholesterol (NP-59) and adrenomedullary imaging with 131I or 123I-labelled metaiodobenzylguanidine (MIBG) as function-dependant imaging techniques provide functional metabolic information for lesion characterization. They enable the distinction between unilateral and bilateral adrenal lesions. Furthermore, they have the advantage of giving the possibility of a whole body evaluation with a single administration of the tracer without additional radiation dose. On the other hand, radiological imaging modalities provide excellent anatomical details which is essential for planning therapy. Both radiological and scintigraphic imaging methods of the adrenal glands are necessary and should, therefore, be considered complementary.

title: Pheochromocytoma: Diagnosis by Scintigraphy Using Iodine 131 Metaiodobenzylguanidine
abstract: We summarize our experience using iodine 131 metaiodobenzylguanidine (131I MIBG) imaging in 24 patients with suspected pheochromocytoma and compare 131I MIBG imaging with other imaging modalities such as computerized tomography and magnetic resonance imaging. Our results confirm the high sensitivity and excellent specificity reported from other centers experienced in 131I MIBG imaging. This radiopharmaceutical permits noninvasive, safe, accurate detection of pheochromocytomas of all types. Iodine 131 MIBG scintigraphy is especially efficacious in the detection of extra-adrenal, recurrent, and metastatic tumors. We review precautions in the screening of patients for 131I MIBG examination, imaging techniques, and drugs that interfere with tumor uptake of 131I MIBG. Though 131I MIBG imaging has some limitations, it deserves strong consideration whenever the diagnosis of pheochromocytoma is suspected.

title: New approach to the localisation of phaeochromocytoma: imaging with iodine-131-meta-iodobenzylguanidine.
abstract: Thirty eight patients with known or suspected phaeochromocytoma were studied by radioisotope imaging after intravenous administration of iodine-131-meta- iodobenzylguanidine (131I- mIBG ), a radiopharmaceutical which has affinity for chromaffin tumours. Seventeen positive results (including one false positive) and 21 negative results (including two false negatives) were obtained. Clinical accuracy was 92%. Urinary noradrenaline concentrations were raised in all patients with confirmed phaeochromocytoma. These findings show that 131I- mIBG is of value in localising and assessing the extent of chromaffin tumours.

title: Imaging of pheochromocytoma and paraganglioma
abstract: Paragangliomas are tumours that arise within the sympathetic nervous system originating from the neural crest. These tumours can be found anywhere from the neck to the pelvis in locations of sympathetic ganglions. Although in the majority of paragangliomas the diagnosis is based on measuring catecholamines and metabolites in plasma or urine, imaging plays an important preoperative role. Today, there are several morphological and radionuclide imaging methods available that predict tumour localisation and tumour extent and give anatomic information to the surgeon. MRI is the morphological imaging modality of choice in localising pheochromocytomas and extra-adrenal paragangliomas. It provides excellent anatomic detail and has the advantage of lacking ionising radiation. The overall accuracy of computed tomography (CT) in detecting primary adrenal pheochromocytomas is very high, but CT lacks in specificity as difficulties may occur in distinguishing between paragangliomas and other tumour entities. The major advantages of radionuclide imaging are very high specificity and routinely performed whole-body scanning. Furthermore, metabolic imaging is not influenced by artifacts like scar tissue or metallic clips in post-surgical follow-up. Currently, a reported specificity of 99% and a cumulative sensitivity of about 90% in paragangliomas make 123I-MIBG the most important nuclear imaging method. However, 18F-DOPA-PET seems to be a very promising procedure which offers higher accuracy. The higher spatial resolution of PET-scanners enables the detection of small lesions not visualised with 123I-MIBG. Both use of radiolabelled somatostatin analogue like 111In-pentetreotide and 18F-FDG is limited due to low specificity of the tracers and should be restricted to MIBG- and F-DOPA-negative cases.

title: Normal Cerebellar MIBG Localization: Implications in the Interpretation of Delayed Scans
abstract: In the I-131 MIBG scans of 14 patients with neuroblastoma (86%) or pheochromocytoma/paraganglioma (14%) that were studied more than 48 hours after administration of the radiopharmaceutical, 12 (86%) had discernible cerebellar MIBG localization. A few had midbrain or diffuse cerebral uptake as well. None of the patients had cerebellar or other central nervous system signs or symptoms, and the localization is consistent with the known distribution density of central nervous system catecholamine receptors. This suggests that cerebellar MIBG localization is normal in delayed scans and that it should not be confused with neuraxial metastasis of adrenergic neuronal neoplasms.

title: Brain uptake of iodine-131 metaiodobenzylguanidine following therapy of malignant pheochromocytoma.
abstract: Intracranial metaiodobenzylguanidine (MIBG) uptake is occasionally and only faintly visualized on diagnostic studies. Recently, intense normal cerebellar uptake was described on posttherapy MIBG images. Experience at the University of Michigan with posttherapy MIBG scintigraphy of pheochromocytoma was reviewed. The patterns and correlates of intracranial uptake after therapeutic 1-131 MIBG in 25 patients (61 patient treatment encounters) were evaluated by review of records and blinded consensus interpretation of diagnostic and posttherapeutic MIBG scans. Thirty-nine (64%) patient treatment encounters demonstrated at least faint (grade 1) MIBG uptake in one or more brain sites; the most common site was the cerebellum. There was a statistically significant relation between intracranial uptake and 1) size of therapeutic dose and 2) patient age, but no relation between intracranial uptake and gender, body mass index, plasma epinephrine level, plasma norepinephrine level, urine metanephrine level, or the therapy-to-imaging interval. Although the influence of age on the pattern and intensity of intracranial uptake is unexplained, the relation to therapy dose may be explained by the possible generation of MIBG metabolites that can cross the blood-brain barrier (high activity administered and the delay until imaging). Further studies are needed to define mechanisms of intracranial uptake and relation to responses and toxicity after MIBG therapy of neuroendocrine tumors.

title: I‐123 MIBG Scintigraphy in Adults A Report of Clinical Experience
abstract: Thirty-one adult patients with clinical findings suggestive of pheochromocytoma were studied with I-123 MIBG. All patients had images obtained at 24 and 48 hours. Five patients had abnormal uptake proved to be because of H23 MIBG avid tumors. The remaining 26 patients had no proven tumors and showed physiologic uptake in various organs. The 24-hour images were of high quality. In all cases, the 48-hour images contributed no significant additional information. Only in 1 patient did the 48-hour image add some certainty. Physiologic uptake was seen in the salivary glands, liver, G.I. tract, and urinary bladder in all patients (100%). Uptake was also observed in the lung and heart (90%), normal adrenal glands (32%), thyroid (29%), spleen (23%) uterus (13%), and neck muscles (6%). The authors' experience indicates that I-123 MIBG gives superior images compared to the previously used I-131 MIBG, that the optimum imaging time for adults is 18–24 hours, and that normal distribution patterns including uterine and neck muscle uptake should be familiar to physicians interpreting the studies.

title: Portrayal of pheochromocytoma and normal human adrenal medulla by m-[123I]iodobenzylguanidine: concise communication.
abstract: The radiopharmaceutical m-[131I]iodobenzylguanidine (I-131 MIBG), which is readily taken up by adrenergic vesicles, produces scintigraphic images of pheochromocytomas in man but rarely visualizes normal adrenal glands. Iodine-123 has many potential advantages over I-131 as a radiolabel for MIBG, including shorter half-life, freedom from beta emissions, and increased gamma-camera efficiency. In this study, diagnostic doses of MIBG labeled with I-131 and I-123, with nearly equivalent radiation dosimetry, were compared as imaging agents in eight patients with known or suspected pheochromocytoma. Images of superior quality were obtained with I-123 MIBG, and lesions not visualized using I-131 MIBG were portrayed. In addition, the normal adrenal medullae were visualized on the I-123 MIBG scintigrams in six out of eight patients.

title: Pheochromocytoma and the normal adrenal medulla: improved visualization with I-123 MIBG scintigraphy.
abstract: The radiopharmaceutical iodine 131 metaiodobenzylguanidine (I-131 MIBG) has been shown to locate pheochromocytomas scintigraphically with a false-negative rate of approximately 13%. To improve image quality and reduce the false-negative rate, I-123 was examined as a radioactive label for MIBG, as it has many advantages over I-131, including superior dosimetry and better detection efficiency. Diagnostic doses of 0.5 mCi (18.5 MBq) I-131 MIBG and 10.0 mCi (370.0 MBq) I-123 MIBG with nearly equivalent radiation dosimetries were compared in 18 patients with known or suspected pheochromocytomas. Images of superior quality were obtained with I-123 MIBG in 18 of 18 patients, and in eight cases lesions not visualized on I-131 MIBG scintigraphy were portrayed. A further advantage of I-123 MIBG is that it permits single photon emission computed tomography (SPECT). This was performed in six cases and provided additional information in three cases. The adrenal medullae were definitely visualized using I-123 scintigraphy in eight of 14 patients still possessing adrenal glands, whereas I-131 MIBG images portrayed the adrenal medulla in only one of 14 cases. Five remaining patients had multiple abdominal tumor deposits that were difficult to differentiate from normal adrenal medullae.

title: Methodology and dosimetry in adrenal medullary imaging with iodine-131 MIBG.
abstract: Iodine-131 MIBG scans were performed in 59 patients in order to localize intra- or extra-adrenal pheochromocytomas (pheos), or to visualize hyperplastic adrenal medulla. Images were obtained from the pelvis to the base of the skull on Days 1, 4, and 7 after tracer injection. The 15 patients with histopathologic confirmation of adrenal medullary disease had positive scans. In three of these, the pheos were visible only on images obtained on Day 7. One scan was false negative. After excluding patients with a predisposition to adrenal medullary disease, nine subjects (28%) without verification of pheo displayed adrenal uptake of the radionuclide. Late images produce a low rate of false-negative scans; the background activity diminishes and even small pheos can be detected. In order to increase the quality of late images, 40 MBq [131I]MIBG was used instead of 20 MBq. The dosimetric considerations are discussed.

title: Iodine-131-MIBG scintigraphy in adults: interpretation revisited?
abstract: Iodine-131-metaiodobenzylguanidine (MIBG) scintigraphy is a reliable method used to diagnose pheochromocytoma. Although the adrenal medulla usually is not visualized, faint uptake can be observed in 16% of the patients 48-72 hr after injection of 18.5-37 MBq 131I-MIBG. We recently observed an increase in the frequency of visualization of the adrenal medulla in patients injected with 74 MBq 131I-MIBG. Therefore, we retrospectively evaluated the pattern of uptake and potential changes between 1984 and 1994.



Scintigraphic data from 103 patients referred for suspected pheochromocytoma were reviewed randomly. Data from 19 patients with medullary thyroid carcinoma were analyzed separately. Patients were injected with 74 MBq 131I-MIBG and imaged at 24 hr postinjection, 48 hr postinjection, or both. Adrenal uptake was scored visually as 0 (no visible uptake) and 1 (uptake just visible) to 4 (most intense activity in the picture). Semiquantitative indicies were evaluated for discriminating between normal adrenal medullae and pheochromocytomas. Twenty-seven pheochromocytomas were surgically proven in 25 patients.



A visual score > or =3 was noted in 81% and 90% of the pheochromocytomas at 24 hr and 48 hr postinjection, respectively. From 1984 to 1988, 16% and 31% of adrenal medullae were seen at 24 and 48 hr postinjection, respectively, whereas from 1989 to 1994, 56% and 73% were visualized at 24 and 48 hr postinjection, respectively. Before 1989, the best cutoff criterion to identify a pheochromocytoma, determined from receiver operating characteristic curve analysis, was a score > or =1 at 24 hr and > or =3 at 48 hr postinjection, with a sensitivity and specificity of 92% and 84% at 24 hr and 92% and 99% at 48 hr postinjection. From 1989, the best cutoff was a score > or =3 at both imaging sessions, with a sensitivity and specificity of 82% and 100% at 24 hr and 100% and 97% at 48 hr postinjection. Among the semiquantitative indicies, the adrenal-to-liver and adrenal-to-heart ratios were the best discriminators between normal and pathological adrenals. They were, however, of little use because of the overlap between normal adrenal medullae and pheochromocytomas.



The high rate of visualization of the normal adrenal medulla in this study was related to the larger-than-usual injected dose (74 MBq). Over recent years, however, this rate has been increasing, possibly because of the increased specific activity of 31I-MIBG. Adequate interpretation should take into account that a faint or definite uptake may be visible in more than 50% of normal adrenal medullae.

title: The normal and abnormal distribution of the adrenomedullary imaging agent m-[I-131]iodobenzylguanidine (I-131 MIBG) in man: evaluation by scintigraphy.
abstract: The scintigraphic distribution of m-[131I]iodobenzylguanidine (I-131 MIBG), an adrenal medullary imaging agent, was studied to determine the patterns of uptake of this agent in man. The normal distribution of I-131 MIBG includes clear portrayal of the salivary glands, liver, spleen, and urinary bladder. The heart, middle and lower lung zones, and colon were less frequently or less clearly seen. The upper lung zones and kidneys were seldom visualized. The thyroid appeared only in cases of inadequate thyroidal blockade. The "normal" adrenal glands were seldom seen and faintly imaged in 2% at 24 hr after injection and in 16% at 48 hr, in patients shown not to have pheochromocytomas, whereas intra-adrenal, extraadrenal, and malignant pheochromocytomas usually appeared as intense focal areas of I-131 MIBG uptake at 24 through 72 hr.

title: Neural crest tumors: I-123 MIBG imaging in children.
abstract: To determine 24- and 48-hour distribution of iodine-123 metaiodobenzylguanidine (MIBG) and to establish an optimized pediatric imaging protocol.



Seventy-seven I-123 MIBG scans obtained in 33 children undergoing evaluation for neural crest tumor were reviewed.



Activity in the salivary glands, myocardium, liver, gut, and bladder was demonstrated on almost all scans. Activity was noted in the neck muscles, thyroid gland, and uninvolved adrenal gland in fewer studies. In 20 studies, abnormal uptake was present in the chest or abdomen at 24 and 48 hours, and lesion identification was improved at 48 hours in 12 studies. Detection of skeletal lesions on 14 scans was similar at 24 and 48 hours. Foci of tumor were first detected at I-123 MIBG imaging in nine studies, and in only two patients was tumor involvement initially missed on I-123 MIBG studies.



Distribution of I-123 MIBG on images in children differs from that in earlier descriptions in adults. Images of the torso at 48 hours after injection are a useful adjunct in detection of lesions.

title: 131I/123I-Metaiodobenzylguanidine (MIBG) scintigraphy: procedure guidelines for tumour imaging
abstract: The aim of this document is to provide general information about mIBG scintigraphy in cancer patients. The guidelines describe the mIBG scintigraphy protocol currently used in clinical routine, but do not include all existing procedures for neuroendocrine tumours. The guidelines should therefore not be taken as exclusive of other nuclear medicine modalities that can be used to obtain comparable results. It is important to remember that the The European Association has written and approved guidelines to promote the use of nuclear medicine procedures with high quality. These general recommendations cannot be applied to all patients in all practice settings. The guidelines should not be deemed inclusive of all proper procedures and exclusive of other procedures reasonably directed to obtaining the same results. The spectrum of patients seen in a specialized practice setting may be different than the spectrum usually seen in a more general setting. The appropriateness of a procedure will depend in part on the prevalence of disease in the patient population. In addition, resources available for patient care may vary greatly from one European country or one medical facility to another. For these reasons, guidelines cannot be rigidly applied. These guidelines summarize the views of the Oncology Committee of the EANM and reflect recommendations for which the EANM cannot be held responsible. The recommendations should be taken in the context of good practice of nuclear medicine and do not substitute for national and international legal or regulatory provisions. The guidelines have been reviewed by the EANM Dosimetry Committee, Paediatrics Committee, Physics Committee and Radiopharmacy Committee. The guidelines have been brought to the attention of the National Societies of Nuclear Medicine. E. Bombardieri :M. R. Castellani Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy F. Giammarile Médecine nucléaire, CHLS, Hospices Civils de Lyon, and Faculté de Médecine, Lyon, France C. Aktolun Tiro-Center Tiroid Merkezi, Istanbul, Turkey R. P. Baum PET Center, Bad Berka, Germany A. Bischof Delaloye CHUV, Lausanne, Switzerland L. Maffioli Ospedale Legnano, Milan, Italy R. Moncayo University of Innsbruck, Innsbruck, Austria L. Mortelmans University UZ Gasthuisberg, Louvain, Belgium G. Pepe :A. Chiti (*) Istituto Clinico Humanitas, Rozzano (MI), Italy e-mail: arturo.chiti@humanitas.it S. N. Reske University of Ulm, Ulm, Germany DOI 10.1007/s00259-010-1545-7  (2010) 37:2436–2446  July 2010 resources and facilities available for patient care may vary from one country to another and from one medical institution to another. The present guidelines have been prepared for nuclear medicine physicians and intend to offer assistance in optimizing the diagnostic information that can currently be obtained from mIBG scintigraphy. The corresponding guidelines of the Society of Nuclear Medicine (SNM) and the Dosimetry, Therapy and Paediatric Committee of the EANM have been taken into consideration, and partially integrated into this text. The same has been done with the most relevant literature on this topic, and the final result has been discussed within a group of distinguished experts.

title: Iodine-131 metaiodobenzylguanidine for the locating of suspected pheochromocytoma: experience in 400 cases.
abstract: The efficacy of the newly developed pheochromocytoma-seeking radiopharmaceutical, [131I]MIBG, was examined in the first 400 patients (441 studies) investigated for suspected pheochromocytoma at our institution. The results of [131I]MIBG scintigraphy were classified as true positive, false positive, true negative, and false negative. Using this classification the sensitivity was found to be 78.4% in primary, sporadic pheochromocytoma, 92.4% in malignant pheochromocytoma, and 94.3% in familial pheochromocytoma giving an overall sensitivity of 87.4%. The specificity was 98.9% in primary, sporadic pheochromocytoma, 100% in malignant pheochromocytoma, and 100% in familial pheochromocytoma. The overall specificity was 98.9%. Iodine-131 MIBG scintigraphy was thus found to be a safe, noninvasive, and efficacious technique for the location of pheochromocytomas, especially for those arising from nonadrenal sites, recurring postoperatively, and exhibiting malignant metastatic disease. We find that, where available, [131I]MIBG scintigraphy is the study of choice to initiate the location of suspected pheochromocytoma.

title: Sensitivity of diagnostic and localization tests for pheochromocytoma in clinical practice.
abstract: Although pheochromocytomas are believed to account for fewer than 0.3% of all cases of hypertension, aggressive diagnostic and surgical intervention is recommended whenever a pheochromocytoma is suspected because uncontrolled catecholamine release from the tumors can lead to catastrophic consequences. Many biochemical diagnostic and imaging localization tests exist for detecting pheochromocytomas. We sought to evaluate the sensitivity of these tests used over a 35-year period at a single institution.



Thirty-five patients with complete medical records who had pathologically confirmed pheochromocytomas between 1962 and 1997 at the University of Chicago Hospitals were identified. Sensitivity and 95% confidence intervals were calculated for 12 laboratory diagnostic tests and 5 imaging studies.



The most sensitive laboratory diagnostic tests in our study were plasma total catecholamines (95%) and urine total metanephrines (100%). Testing for urine vanillylmandelic acid, while less expensive and easier to perform than many other tests, had a slightly lower sensitivity (89%). The most sensitive imaging tests in the study were magnetic resonance imaging (100%) and iodine I-131 metaiodobenzylguanidine scintigraphy (100%). The more often used computed tomography had only 88% sensitivity. Localization was safely and successfully performed on two pregnant patients using magnetic resonance imaging and ultrasound.



By properly choosing from the wide array of laboratory diagnostic and imaging tests, pheochromocytomas can be identified and localized with nearly 100% sensitivity. These tests should be performed in any patient for whom the diagnosis of pheochromocytoma is being considered.

title: Radionuclide diagnosis and therapy of neural crest tumors using iodine-131 metaiodobenzylguanidine.
abstract: The successful application of [131I]metaiodobenzylguanidine (MIBG) in diagnosis and therapy of pheochromocytoma has led to its use in other tumors which derive from the neural crest and potentially concentrate this radiopharmaceutical as well. In the present series, [131]MIBG total-body scintigraphy was used for detection of neuroblastoma in 47 patients and 47 cases of other neural crest tumors. The method was found to be as reliable in neuroblastoma (sensitivity 95%, specificity 100%), as it is in pheochromocytoma. Although other neural crest tumors may concentrate [131I]MIBG, this is not a consistent finding; however, it is useful to investigate which tumors do, as this may provide an alternative treatment modality for some patients. Although followup is still very short, preliminary results of therapeutic use of [131I] MIBG in 21 patients indicate that this treatment modality may be effective in neuroblastoma and malignant pheochromocytoma.

title: Complementary roles of CT and 131I-MIBG scintigraphy in diagnosing pheochromocytoma.
abstract: Recently 131I-MIBG (metaiodobenzylguanidine), an adrenergic tissue-localizing radiopharmaceutical, has been used for diagnosis of pheochromocytoma. In a retrospective study of 32 patients with pathologically proved primary, metastatic, or recurrent pheochromocytoma, the roles of 131I-MIBG scintigraphy and computed tomography (CT) in pheochromocytoma detection were compared. The two methods were equally accurate in the identification of primary and recurrent pheochromocytoma. 131I-MIBG scanning was more accurate as the initial examination in patients with extraadrenal tumors. In patients with metastatic disease, scintigraphy was preferable to CT because of its nontomographic nature, which permitted imaging of the entire body. Although a positive MIBG scan is diagnostic of pheochromocytoma, CT of extraadrenal tumors (particularly in the chest) has been very useful in planning appropriate surgical intervention. Furthermore, the roles of 131I-MIBG scintigraphy and CT in the detection of pheochromocytoma are complementary because each method has certain limitations.

title: Utility of thallium-201 and iodine-123 metaiodobenzylguanidine in the scintigraphic detection of neuroendocrine neoplasia
abstract: Metaiodobenzylguanidine (MIBG) is a specific marker for neuroendocrine tumours, such as phaeochromocytoma, neuroblastoma, medullary thyroid cancer (MTC) and paraganglioma, but it suffers in some cases (especially in MTC) from a lack of sensitivity. Thallium is a well-known marker of cellularity with a great sensitivity and a lack of specificity. In order to determine whether the association of these two markers is able to improve the detection of neuroendocrine lesions, 137 scintigraphic examinations using MIBG and thallium were performed in 101 patients referred for suspicion or follow-up of neuroendocrine tumours. Thallium chloride was first injected (1 MBq/kg), images being acquired about 20 min after injection; 123I-MIBG (4 MBq/kg) was then injected and images acquired 5 and 24 h later. In patients with phaeochromocytoma or neuroblastoma, thallium scintigraphy appeared of little help since no tumoural site was discovered by thallium accumulation alone. In contrast, thallium examination seemed of interest in the detection of paraganglioma and MTC, the association of the two radiopharmaceuticals increasing the number of detected sites.

title: 123I‐metaiodobenzylguanidine (MIBG) scintigraphy for the detection of adrenal and extra‐adrenal phaeochromocytomas: CT and MRI correlation
abstract: Evidence regarding the accuracy of [123I] metaiodobenzylguanidine (MIBG) imaging for phaeochromocytoma localization is currently limited to small series.

title: 111In-Octreotide Is Superior to 123I-Metaiodobenzylguanidine for Scintigraphic Detection of Head and Neck Paragangliomas
abstract: In this study, we evaluated the diagnostic yield of somatostatin receptor scintigraphy (SRS), I-metaiodobenzylguanidine (MIBG) scintigraphy, and morphologic imaging (CT or MRI) in patients with head and neck paragangliomas.  In a university hospital setting, patients considered to have head and neck paraganglioma were referred to the outpatient endocrinology department and underwent CT or MRI, SRS, and MIBG imaging. For validation, we used a composite reference standard consisting of clinical and histologic data and CT or MRI, with which SRS and MIBG imaging were compared. Urinary metanephrine and normetanephrine measurements were also obtained.  Twenty-nine consecutively referred patients (17 women and 12 men) were included and were found to have paraganglioma. Both morphologic and SRS were positive in 27 patients (sensitivity, 93%, and 95% confidence interval [CI], 77%–98%, compared with the composite reference standard), whereas MIBG was positive in only 13 patients (44%; 95% CI, 23%–61%) (P < 0.001, compared with SRS). On a lesion-based analysis, morphologic imaging detected 31 lesions (sensitivity, 82%; 95% CI, 65%–92%), SRS detected 34 (89%; 95% CI, 75%–97%), and MIBG detected 15 (42%; 95% CI, 26%–59%). SRS was superior to MIBG (P = 0.001). With SRS, a previously unknown carcinoid tumor was detected in 1 patient, and a carcinoid was suspected in another patient. MIBG detected an additional adrenal pheochromocytoma in 1 patient. Urinary metanephrine or normetanephrine excretion was elevated in 6 patients. The number of lesions on SRS and MIBG per patient correlated with the levels of abnormal metanephrine or normetanephrine excretion (P = 0.005 and P = 0.02, respectively).  SRS was superior to MIBG in patients with highly suspected head and neck paraganglioma.

title: Usefulness of 123I-MIBG Scintigraphy in the Evaluation of Patients with Known or Suspected Primary or Metastatic Pheochromocytoma or Paraganglioma: Results from a Prospective Multicenter Trial
abstract: Although 123I-MIBG has been in clinical use for the imaging of pheochromocytoma for many years, a large multicenter evaluation of this agent has never been performed. The present study was designed to provide a prospective confirmation of the performance of 123I-MIBG scintigraphy for the evaluation of patients with known or suspected primary or metastatic pheochromocytoma or paraganglioma.  A total of 81 patients with a prior history of primary or metastatic pheochromocytoma or paraganglioma and 69 with suspected pheochromocytoma or paraganglioma based on symptoms of catecholamine excess, CT or MRI findings, or elevated catecholamine or metanephrine levels underwent whole-body planar and selected SPECT 24 h after the administration of 123I-MIBG. Images were independently interpreted by 3 masked readers, with consensus requiring agreement of at least 2 readers. Final diagnoses were based on histopathology, correlative imaging, catecholamine or metanephrine measurements, and clinical follow-up.  Among 140 patients with definitive diagnoses (91, disease present; 49, disease absent), 123I-MIBG planar scintigraphy had a sensitivity and specificity of 82%. For patients evaluated for suspected disease, sensitivity and specificity were 88% and 84%, respectively. For the subpopulations of adrenal (pheochromocytoma) and extraadrenal (paraganglioma) tumors, sensitivities were 88% and 67%, respectively. The addition of SPECT increased reader confidence but minimally affected sensitivity and specificity.  This prospective study demonstrated a sensitivity of 82%−88% and specificity of 82%−84% for 123I-MIBG imaging used in the diagnostic assessment of primary or metastatic pheochromocytoma or paraganglioma.

title: Whole-body PET/CT with 11C-meta-hydroxyephedrine in tumors of the sympathetic nervous system: feasibility study and comparison with 123I-MIBG SPECT/CT.
abstract: 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.

title: Added value of SPECT/CT for correlation of MIBG scintigraphy and diagnostic CT in neuroblastoma and pheochromocytoma.
abstract: In pheochromocytoma and neuroblastoma, pathologic findings on metaiodobenzylguanidine (MIBG) scintigraphy (planar and SPECT) and on diagnostic CT are sometimes difficult to correlate. Furthermore, CT reading may be impaired by anatomic distortion after surgery or irradiation and if contrast agent is not injected. The present study evaluates the impact of SPECT/CT fusion images on correlation and image analysis of both techniques.



Eleven patients, three adults (age range, 27-64 years) with pheochromocytoma and eight children (age range, 16-72 months) with neuroblastoma, underwent 15 (123)I-MIBG scintigraphy (whole body and SPECT/CT) and diagnostic CT during follow-up after treatment, with a time interval of 2 to 30 days (mean, 12 days) between MIBG scintigraphy and diagnostic CT. The diagnostic CT scans were read twice: blindly and with knowledge of the SPECT/CT findings. The scintigraphic and anatomic data were subsequently compared and were verified by clinical outcome.



Of 15 imaging studies, there were nine cases of discordance between SPECT/CT and diagnostic CT, whereas concordant findings of planar MIBG and diagnostic CT were observed in six studies. Overall, SPECT/CT provided additional information in eight of the 15 cases (53%) and in eight of nine discordant studies (89%). In one case of pheochromocytoma in which anatomy was distorted by previous surgery and contrast agent was not injected, SPECT/CT findings guided the diagnostic CT that had initially misinterpreted the right adrenal gland as the inferior vena cava. In three of 11 studies performed for neuroblastoma, SPECT/CT facilitated the diagnostic CT reading: in one study, a small paravertebral thickening was overlooked at blind CT reading and in another case, SPECT/CT localized and characterized a soft-tissue mass medial to the iliac bone, which was missed on diagnostic CT in an area of difficult differential anatomy (bowel loops and eventual involved lymph nodes). In the third case, SPECT/CT directed the diagnostic CT to the MIBG abnormality after multiple surgical procedures. In these four cases, MIBG SPECT/CT allowed for localization of the pathologic site that was difficult to visualize on diagnostic CT. In four additional neuroblastoma studies in which a residual mass was present on diagnostic CT, planar MIBG scintigraphy was negative. SPECT/CT, focused on the area of the diagnostic CT abnormality, showed no focal MIBG uptake, thus increasing the diagnostic certainty of remission.



In cases of equivocal diagnostic CT, SPECT/CT bridges the gap between MIBG scintigraphy and diagnostic CT, with guidance of the diagnostic CT and characterization of its findings. In this small series, MIBG SPECT/CT increased the diagnostic certainty in 89% of discordant studies.

title: Value of combined XCT/SPECT technology for avoiding false positive planar (123)I-MIBG scintigraphy.
abstract: The clinical value of combined XCT/SPECT technology in a single device in patients undergoing (123)I-MIBG scintigraphy was analyzed.



31 patients (19 men, 12 women; mean age 55 years, range: 31-79 years) demonstrating focal accumulation in planar (123)I-MIBG scan were further investigated with a double headed gamma camera with an X-ray tomograph mounted on the same gantry (GE Medical Systems, Millennium VG with Hawkeye, Milwaukee, USA) for anatomical definition of the focal (123)I-MIBG uptake. The patients were referred to (123)I-MIBG scintigraphy because of biochemically (81%) and/or clinically (19%) suspected pheochromocytoma.



In 23 out of 31 patients (74%) the fused images demonstrated physiological accumulation (i. e. intestinal, renal) of (123)I-MIBG. In two patients (6%) suspected adrenal MIBG-accumulation was caused by inhomogeneous liver uptake. In two patients (6%) focal abdominal accumulation was correctly localised in the adrenal glands. Furthermore, the differentiation of bone metastasis from a local recurrence for phaeochromocytoma was accurately possible for two patients (6%). Adrenal lesions mimicking liver foci were correctly localised in the remaining two patients (6%).



Our study demonstrates the clinical value of XCT/SPECT in a single device in patients demonstrating focal (123)I-MIBG uptake in planar scintigraphy. The combined XCT/SPECT technology provides a higher diagnostic accuracy.

title: Diagnosis of pheochromocytoma using [123I]‐ compared with [131I]‐metaiodobenzylguanidine scintigraphy
abstract: Patient with pheochromocytoma (PCT) cannot be cured without operation, therefore, preoperative determination of the localization of PCT should be performed accurately.  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.

title: Sensitivity and positive predictive value of CT, MRI and 123I-MIBG scintigraphy in localizing pheochromocytomas: A prospective study
abstract: AimTo establish a standardized non-invasive imaging protocol for patients with pheochromocytoma undergoing surgery. MethodsA series of 32 consecutive patients (16 men, 16 women; median age 43 years, range 15–71 years) with biochemically confirmed pheochromocytoma underwent computed tomography (CT) scanning, magnetic resonance imaging (MRI) and meta-[123I]iodobenzylguanidine (MIBG) whole-body scintigraphy prior to adrenalectomy or excision of extra-adrenal tumour (paraganglioma). ResultsAt final pathology no malignant pheochromocytomas were found. The tumour was right-sided in 16 (50%) patients, left-sided in 13 (41%), extra-adrenal (sympathetic ganglia, upper abdomen) in two (6%) and bilateral in one (3%) patient. Overall, the median greatest diameter (size) of the tumour was 35 mm (range, 15–90 mm). The sensitivity of CT, MRI and MIBG scintigraphy was 90%, 93% and 91%, and the specificity was 93%, 93% and 100%, respectively. The three patients with false negative scintigraphy had an intra-adrenal tumour, ranging from 20 to 50 mm in size. The presence of necrosis within the mass might justify the lack of significant uptake of radiopharmaceutical in two patients, and the small size (15 mm) of the mass in the other. There were two false positive results with both CT and MRI, and no false positive MIBG scintigraphy, which had the highest (100%) positive predictive value. The combination of MRI+MIBG scintigraphy reached 100% sensitivity and positive predictive value. ConclusionOur data suggest that this imaging protocol should be used in all patients with biochemically confirmed pheochromocytoma.

title: A meta-iodobenzylguanidine scintigraphic scoring system increases accuracy in the diagnostic management of pheochromocytoma.
abstract: As observed by other authors, normal adrenal medullary tissue frequently gives an apparently positive meta-iodobenzylguanidine (MIBG) scan in cases studied using 123I-MIBG and less frequently 131I-MIBG. The aim of this study was to assess the usefulness of a scoring system, based on different uptakes of the radiopharmaceutical, to improve the accuracy of 123I-MIBG scintigraphy in patients with either adrenal or extra-adrenal pheochromocytomas. Charts from 67 consecutive patients (29 males and 38 females, median age 48 years, range 14-80 years) with suspected pheochromocytoma (either sporadic or familial: multiple endocrine neoplasia (MEN) 2a, MEN2b, Von Hippel-Lindau, neurofibromatosis type 1) who underwent 123I-MIBG scintigraphy (scans acquired 4-24 h after injection) from 1991 to 2004, were independently reviewed by two experienced nuclear medicine physicians using liver uptake as a reference (scores: 1, uptake absent or less than the liver; 2, equal to the liver; 3, moderately more intense than the liver; 4, markedly more intense than the liver). Interfering medications were discontinued for the appropriate time before MIBG injection. Histological data were obtained for all patients who underwent adrenalectomy. Scintigraphies were classified as positive using the following criteria: extra-adrenal focal uptake, adrenal enlargement together with non-homogeneous uptake and adrenal uptake more intense than the liver (score 3-4). After surgical resection, as confirmed by histological findings and long-term follow-up (range 1-14 years, average 9.25 years), 43 patients were considered true positives using the proposed scoring system, 20 were true negatives, four were false negatives and none was false positive. In conclusion, the proposed scoring system demonstrated high specificity (100%), sensitivity (91.5%) and accuracy (94%) in the management of pheochromocytoma. Positive predictive value and negative predictive value were 100% and 83.3% respectively. Normal adrenal tissue uptake was correctly discriminated from pheochromocytomas in 18 out of 20 patients, with adrenal uptake equal to the liver (grade 2), using the proposed cut-off level.

title: Location of adrenal medullary pheochromocytoma by I-123 metaiodobenzylguanidine SPECT.
abstract: This is a retrospective study evaluating the efficacy of SPECT in the location of pheochromocytoma. Thirty patients with a suspected pheochromocytoma underwent I-123 metaiodobenzylguanidine (I-123 MIBG) SPECT 4 and 22 hours after intravenous injection of 370 MBq I-123 MIBG. SPECT was compared with planar scintigraphy, CT scanning, histology, and clinical course. Twenty-two-hour I-123 MIBG SPECT correctly identified 10 patients with adrenal medullary pheochromocytoma and correctly excluded pheochromocytoma in 19 patients. The sensitivity of the 22-hour MIBG SPECT was 1.00 and the specificity was 0.95. The positive predictive value was 0.95 and the negative predictive value was 1.00. In 16 patients, planar scintigraphy was compared with SPECT. SPECT located normal adrenal glands and tumors with greater confidence in three dimensions, but the patients with adrenal medullary pheochromocytoma were all correctly identified by planar scintigraphy. The results of SPECT and CT agreed in 29 of 30 patients (96.7%). I-123 MIBG SPECT for the location of pheochromocytoma has a high sensitivity, specificity, and positive and negative predictive values. I-123 MIBG SPECT or CT scanning alone were equally good for locating adrenal medullary pheochromocytoma but the combination of MIBG SPECT and CT makes it possible to distinguish between functioning and nonfunctioning adenomas. I-123 MIBG SPECT may be used alone or in combination with planar scintigraphy when three-dimensional location of a lesion is wanted.

title: Primary Extra-Adrenal Pheochromocytoma Positive I-123 MIBG Imaging with Negative I-131 MIBG Imaging
abstract: I-131 metaiodobenzylguanidine (I-131 MIBG) is a well established imaging agent that reliably detects pheochromocytoma. In some patients, however, I-131 MIBG may fail to localize pheochromocytoma. I-123 MIBG has several potential advantages over I-131 MIBG, and these advantages may enable locating pheochromocytomas which have eluded other techniques, including I-131 MIBG imaging. A patient with primary extraadrenal pheochromocytoma is described who illustrates the superiority of I-123 MIBG for the imaging of pheochromocytoma.

title: Diagnostic localization of extra-adrenal pheochromocytoma: comparison of (123)I-MIBG imaging and (131)I-MIBG imaging.
abstract: The accurate diagnostic localization of extra-adrenal pheochromocytoma is important in the treatment of primary and metastatic tumors. In this study, we report on a case of extra-adrenal pheochromocytoma in which the tumor could not be diagnosed by 131I-metaiodobenzylguanidine (MIBG) scintigraphy but only by 123I-MIBG scintigraphy. Our patient was a 16-year old girl whose chief complaint was headaches. High levels of catecholamines were detected in the blood and urine samples. 131I-MIBG scintigraphy could not detect any abnormal accumulation, but an accumulation of 123I-MIBG was found in the pelvis. Magnetic resonance imaging (MRI) revealed a broad-based bladder tumor at the site of the accumulation. Partial cystectomy was performed, and immunohistochemical staining examination confirmed the diagnosis of extra-adrenal pheochromocytoma in the urinary bladder. In this report, we compare 131I-MIBG scintigraphy with 123I-MIBG scintigraphy and discuss their characteristics.

title: Detection and treatment of pheochromocytomas and paragangliomas: current standing of MIBG scintigraphy and future role of PET imaging.
abstract: Pheochromocytomas are rare tumors arising from chromaffin cells of adrenal medullary or extra-adrenal paraganglionic tissue. These tumors are characterized by synthesis, storage, metabolism and secretion of catecholamines. Similar to the sympathetic nervous system, pheochromocytomas express cellular norepinephrine transporters (NET) through which catecholamines can enter pheochromocytoma cells to be stored in vesicles. Metaiodobenzylguanidine (MIBG) resemblance to norepinephrine and its good affinity and uptake by NET resulted in its use in pheochromocytoma diagnosis from 1981. Both [(123)I]MIBG and [(131)I]MIBG (lower sensitivity) scintigraphy are used for localization of these tumors. Recent discoveries of different hereditary syndromes associated with pheochromocytomas led to the identification of several and new distinct genotype-phenotype associations. Importantly, with this distinction of clinical phenotypes, MIBG was found to have a different performance in subsets of pheochromocytoma patients. Reduced sensitivity of MIBG scintigraphy in some familial paraganglioma syndromes, malignant disease and extra-adrenal paragangliomas has been found. Therefore, newer compounds, especially for positron emission tomography (PET), such as [(11)C]hydroxyephedrine ([(11)C]HED), [(18)F]fluoro-2-deoxy-D-glucose ([(18)F]FDG), [(18)F]fluoro-dihydroxyphenylalanine ([(18)F] FDOPA) and [(18)F]fluorodopamine ([(18)F]FDA) have emerged and were found to be superior to MIBG in the localization of certain types of pheochromocytoma and paragangliomas. Finally, using [(131)I]MIBG represents an important treatment option in patients with malignant pheochromocytoma, but the development of newer treatment modalities is expected. In this review, we provide the reader with an overview of the current standing of [(123)I]- and [(131)I]MIBG in diagnosis and treatment of pheochromocytoma amongst the newer PET imaging agents.

title: Tumour size: the only predictive factor for 131I MIBG uptake in phaeochromocytoma and paraganglioma.
abstract: 131I Meta-iodobenzylguanidine (131I MIBG) scintigraphy can detect chromaffin tumours with a high specificity but its sensitivity remains limited. In this study, the influence of clinical features and tumour pathology on the results of 131I MIBG of patients with phaeochromocytomas and paragangliomas was examined.



The records of 104 patients operated on for chromaffin tumours who had pre-operative 131I MIBG were reviewed. Demographic data, clinical features, biochemical results and pathology of tumours were analysed. The size of the tumour was assessed by the three measured diameters of the specimen and its calculated volume. Univariate relationship between tumours' characteristics and the results of 131I MIBG were examined.



Out of 119 tumours, 104 (87%) were detected by 131I MIBG. Mean +/- SD largest diameter and volume of the tumours were 6.0 +/- 2.4 cm (range 0.8-11.5 cm) and 68 +/- 74 cm3 (range 0.2-421 cm3). Results of 131I MIBG were significantly correlated with both the largest diameter of the tumour (P < 0.01) and by its volume (P < 0.001). 131I MIBG was negative in 35.5% of tumours < 20 cm3 and in 2.6% of those < 20 cm3. No other criteria were correlated with positive 131I MIBG, including aetiology, pathology or catecholamine secretion pattern.



The result of 131I MIBG scanning in patients with chromaffin tumours is significantly correlated with the size of the tumour.

title: Diagnostic imaging in patients with paragangliomas. Computed tomography, magnetic resonance and MIBG scintigraphy comparison.
abstract: We compared iodine-131 metaiodobenzylguanidine (MIBG), computed tomography (CT) and magnetic resonance (MR) imaging studies in 40 patients with suspected or proven paragangliomas.



21 patients were studied during the initial evaluation, while 19 were evaluated after surgery for paragangliomas. Furthermore, in 18 patients with benign (n = 10) or malignant (n = 8) tumors, MIBG uptake, MR signal intensity ratios (SIR) and CT parameters were analyzed.



In patients studied during the initial evaluation, CT and MR had a significant (p < 0.05) higher diagnostic sensitivity (100% for both) compared to MIBG (82%); conversely, MIBG showed a higher specificity (100%) compared to CT and MR (50% for both); the accuracy of MIBG (86%), CT and MR (91% for both) were similar. In patients evaluated after surgery, MIBG and MR had slightly better sensitivity (85% for both) compared to CT (77%). MIBG showed again better specificity (100%) than CT and MR (83% for both); the accuracy of MIBG, MR and CT were respectively 90%, 84% and 79%. While no significant differences were observed in MR SIR and CT findings between benign and malignant tumors, MIBG uptake was significantly higher in malignant compared to benign lesions (p < 0.03).



Our results suggest that CT and MR are particularly useful in the initial evaluation of patients with suspected paragangliomas. MIBG should be recommended during the post-surgical follow-up of such patients since recurrent, malignant or extra-adrenal disease frequently occur. Finally, while MR SIR and CT features are not able to distinguish malignant paragangliomas from benign tumors, MIBG uptake is higher in malignant lesions compared to benign tumors providing a diagnostic criterion to differentiate these lesions.

title: Pheochromocytoma: study of 50 cases.
abstract: We studied the clinical picture, sensitivity of the biochemical tests and imaging studies, pathological findings, surgical results and followup of patients with pheochromocytoma.



The records of 50 patients with pheochromocytoma were identified. Hyperadrenergic symptoms and signs; urinary dopamine, epinephrine, norepinephrine and vanillylmandelic acid levels; serum dopamine, epinephrine and norepinephrine levels; ultrasonography; computerized tomography; magnetic resonance imaging and 131iodine-metaiodobenzylguanidine images were analyzed. The size, weight and malignancy of the tumors, as well as the operative mortality, survival rate and clinical condition of the patients were also studied.



The hyperadrenergic syndrome alone was found in 90% of the patients, Cushing's syndrome alone in 2%, both syndromes in 4%, a palpable abdominal tumor only in 2% and incidental tumors in 2%. The sensitivities of the urinary evaluation in the diagnosis were metanephrines 97%, vanillylmandelic acid 90%, epinephrine 64%, norepinephrine 93% and dopamine 66%. For serum assessment the sensitivities were epinephrine 67%, norepinephrine 93% and dopamine 63%. The sensitivities of the localization examinations were 89, 94, 100 and 88% for ultrasonography, computerized tomography, magnetic resonance imaging and 131I-metaiodobenzylquanidine, respectively. There was only 1 operative death. Of the patients with benign tumors 88% were cured and 12% remained hypertensive with no clinical or biochemical evidence of a hyperadrenergic profile. Of the 8 patients with malignant pheochromocytoma 1 was lost to followup and 3 died of widespread disease (1 without surgery and at 2, 24 and 78 months postoperatively). Of the 4 living patients 3 had no evidence of disease and 1 was well, although with pulmonary metastases.

title: The efficacy of iodine-123-MIBG as a screening test for pheochromocytoma.
abstract: The primary objective of this study was to characterize the effectiveness of 123I-metaiodobenzylguanidine (MIBG) as a screening test for pheochromocytoma in routine clinical practice. An attempt was made to determine why some tumors and some adrenal glands without pheochromocytoma minimally manifest increased uptake.



Planar images were obtained with a standardized protocol in a diverse group of patients. The intensity of uptake in each adrenal gland was graded on a 0-3-point scale by using the intensity of activity in the liver as a reference. Follow-up data were obtained from both the patients and the referring physicians. A final diagnosis was eventually established in 120 patients who had a total of 238 adrenal glands.



There was an intramedullary pheochromocytoma in 24 of the 238 adrenal glands (10.1%). The uptake was very intense (Grade 3) in 21 of them (87.5%). The uptake was only mildly to moderately increased in the other three intra-adrenal tumors. There was no visible uptake in 148 of the 214 (69.2%) adrenals without a pheochromocytoma, but there was mildly to moderately increased activity in 66 (30.8%). There were no other features of the clinical data base which could differentiate between mildly increased uptake in a pheochromocytoma and mildly increased activity in a gland without a tumor, including the 24-hr urinary excretion of catecholamines.



Since every intra- and extra-adrenal tumor was visualized, the findings suggest that 123I-MIBG may be the most sensitive screening test available for diagnosing pheochromocytoma. The test results should be definitive in most patients.

title: Localization of Pheochromocytoma: 131i-MIBG Scintigraphy Correlated with Computed Tomography
abstract: Received 11/13/2000; revised 2/1/2001; accepted 2/5/2001. For correspondence or reprints contact: Chiang-Hsuan Lee, M.D., Department of Nuclear Medicine, Chang Gung Memorial Hospital, 123, Ta-Pei Road, Niao Sung Hsiang, Kaohsiung Hsien, Taiwan, Tel: (886)7-7317123 ext. 2627, Fax: (  This study aimed to evaluate the efficacy of iodine-131 meta-iodobenzylguanidin (I-MIBG) scintigraphy and computed tomography (CT) in localization of pheochromocytomas.  We retrospectively evaluated 25 patients with pheochromocytomas in our hospital during 1987-1999. All of these patients received I-MIBG scintigraphy and CT examinations within one week. The pathologic confirmations were obtained in all of the patients.  Pheochromocytomas were localized in unilateral adrenal gland in 22 patients (88%) and in extraadrenal in 3 patients (12%). Overall sensitivity of the studies was 96% (24/25) for CT and 80% (20/25) for MIBG. CT failed to detect one perivesical lesion, and falsely detected two other lesions as pheochromocytomas (specificity 92%). MIBG scintigraphy failed to detect five lesions; three of these lesions were imaged while the patients were on labetalol therapy and the other two lesions were smaller than 3 3 3 cm in size. There were no false positive results by MIBG scintigraphy (specificity 100%). Combined use of these two imaging procedures correctly detected all of these pheochromocytomas.  MIBG scintigraphy and CT are complementary in the localization of pheochromocytoma. CT has greater sensitivity than MIBG scintigraphy in abdomen sites. However, MIBG scintigraphy can provide specific functional confirmation of the CT findings and has the ability to screen the entire body, which is especially useful in the detection of extra-abdominal disease.

title: Comparison of image quality of different iodine isotopes (I-123, I-124, and I-131).
abstract: I-131 is a frequently used isotope for radionuclide therapy. This technique for cancer treatment requires a pre-therapeutic dosimetric study. The latter is usually performed (for this radionuclide) by directly imaging the uptake of the therapeutic radionuclide in the body or by replacing it by one of its isotopes, which are more suitable for imaging. This study aimed to compare the image quality that can be achieved by three iodine isotopes: I-131 and I-123 for single-photon emission computed tomography imaging, and I-124 for positron emission tomography imaging. The imaging characteristics of each isotope were investigated by simulated data. Their spectrums, point-spread functions, and contrast-recovery curves were drawn and compared. I-131 was imaged with a high-energy all-purpose (HEAP) collimator, whereas two collimators were compared for I-123: low-energy high-resolution (LEHR) and medium energy (ME). No mechanical collimation was used for I-124. The influence of small high-energy peaks (>0.1%) on the main energy window contamination were evaluated. Furthermore, the effect of a scattering medium was investigated and the triple energy window (TEW) correction was used for spectral-based scatter correction. Results showed that I-123 gave the best results with a LEHR collimator when the scatter correction was applied. Without correction, the ME collimator reduced the effects of high-energy contamination. I-131 offered the worst results. This can be explained by the large amount of septal penetration from the photopeak and by the collimator, which gave a low spatial resolution. I-124 gave the best imaging properties owing to its electronic collimation (high sensitivity) and a short coincidence time window.

title: Evaluation of collimator choice and scatter correction on 123I SPECT images
abstract: To compare the performance of low-energy (LE) and medium-energy (ME) collimators and the use of scatter correction on 123 I SPECT images as assessed by visual inspection and semi-quantitative analysis.  Both brain and heart/thorax phantoms were used to evaluate the effects of collimator selection and correction methods on brain and cardiac 123 I imaging. Experiments were performed to measure the target-to-background ratio for calculation of object contrast. The projection data were corrected using X-ray-based attenuation maps for attenuation correction (AC) and dual-energy window method for scatter correction (SC). Reconstructed images using different methods were compared, which included FBP (filtered backprojection), and OSEM (ordered subsets expectation maximization) without any correction, with AC, with SC, and with AC and SC.  In both phantom studies, the image contrasts provided by the ME collimator were better than that of the LE collimator. The OSEM with simple dual-energy window SC method improved image contrast and visual image quality as compared to the FBP method. The use of AC improved the visual image quality but did not improve image contrast, if SC method was not implemented at the same time.  This study demonstrates the importance of SC and ME collimator in 123 I SPECT imaging. If image contrast is the figure of merit, then SC should be performed and the use of the ME collimator appears to be preferable in semi-quantitative 123 I SEPCT studies.

title: Influence of high-energy photons on the spectrum of iodine-123 with low- and medium-energy collimators: consequences for imaging with 123I-labelled compounds in clinical practice
abstract: Using iodine-123 labelled radiotracers, the presence of 2.5% high-energy photons causes image deterioration due to increased scatter. To investigate the influence of these photons on image quality, we measured the spectrum of 123I with a medium-energy (ME), a low-energy all-purpose (LEAP) and a low-energy high-resolution (LEHR) collimator. Even in air, using low-energy collimators a high baseline activity was observed over the total energy detection range of the gamma camera. The 159-keV photopeak to scatter activity ratio fell from 5.9 for ME to 3.6 and 2.9 for LE collimators. Acquisition of images with LEHR collimators with energy windows set at 159 keV and 500 keV demonstrated that the 159-keV LEHR image is a combination of the ME image of the object and of the LEHR 500-keV image. Because of their important septal penetration and greater geometric detection efficiency compared with the 159-keV photons of 123I, the contribution of high-energy photons is dependent on the source-detector distance. For a small source placed in air, the scatter to photopeak activities varied from 17.4% at 80 cm to 37.8% at 5 cm distance from an LEHR collimator. Considering only the scatter problem, ME collimators are the best choice for 123I studies. When using LE collimators for high-resolution tomography with 123I-labelled compounds, scatter contribution from high-energy photons has to be corrected for quantitative analysis or when dual-isotope studies are performed, whether or not these studies are acquired simultaneously.

title: Pheochromocytoma: new concepts and future trends.
abstract: A 37-year-old white woman was referred to the Cleveland Clinic Foundation for evaluation of a right suprarenal mass. BeginningS years before, she had experienced episodes of severe headache, pounding heart, and flushing, followed by facial pallor and tremulousness. Neither blood pressure nor heart rate was checked during these spells. The attacks occurred about twice monthly and lasted for 5 to 20 minutes. She noted that "bearing down" during defecation or "curling up" on her left side often precipitated these episodes. She consulted 6 physicians over the subsequent 4 years; no diagnosis was made to explain her symptoms. One year ago, she consulted a neurologist, who performed a thorough examination and obtained a magnetic resonance image of the head: no abnormalities were detected. One month before she came to the Cleveland Clinic, her private physician obtained an abdominal sonogram because he suspected an abdominal aneurysm. The study revealed a "5.2 x 5.1 cm solid, hyperechoic suprarenal mass" on the right side. Neither she or her family had a significant medical history. Physical examination revealed a blood pressure of 122/76 mm Hg: pulse, 80 beats/mm and regular: and respiratory rate, 16/mm. The rest of the examination was unremarkable. Laboratory studies revealed: normal SMA-l6 values except for a blood glucose of 133 mg/dl: normal thyroid function: serum calcium. 8.8 mg/dl; plasma norepinephrine. 1456 pg/mI: epinephrine. 259 pg/mI; 24-hr urinary metanephrine, 5728 g/24 hr: normetanephrine, 10,465 g/24 hr; and serum chromogranin A, 162 ng/ml (normal. 50 ng/ml). An abdominal CT scan revealed a right suprarenal mass measuring about 6.0 cm diameter, which demonstrated a high signal intensity on the T2-weighted image by MRI . The mass concentrated high

title: Pheochromocytoma in Italy: a multicentric retrospective study.
abstract: To conduct an epidemiological study on pheochromocytoma in Italy.



Data on 284 patients with pheochromocytoma observed between 1978 and 1997 were collected from 18 Italian centers through a questionnaire reporting epidemiological, clinical, laboratory, radiological and surgical data.



53.6% of the patients were females and 46.4% were males. Thirty-two tumors were discovered as incidental adrenal masses. The most frequent referred symptoms were palpitations (58.1%), headache (51.9%), sweating (48. 8%) and anxiety (35.3%). Their association was present only in 15.5% of patients. Paroxysmal symptoms were reported in 67.1% and hypertensive crises in 59.7% of patients. Normal blood pressure (systolic and diastolic) was present both in the supine and upright positions in 21.1% of patients. Among laboratory assays, urinary vanylmandelic acid (VMA) was the most widely used (58.1%) and was the least sensitive (25% of false negative results). Basal plasma catecholamines were found to be normal in 11.3% of patients but were always elevated when sampled during a hypertensive paroxysm. A clonidine suppression test was performed in 38 patients with no adverse side effects. It gave a false negative response in 2 patients. A glucagon test was performed in 21 patients. It was interrupted for acute hypertension in 52.4% of patients. Only 5/21 patients were normotensive and had normal basal plasma catecholamines. In these patients the test gave a positive response in four (80%). CT (79.6%) and I-MIBG scintigraphy (68.5%) were the most widely used methods for tumor localization. CT sensitivity was 98.9% for intra-adrenal and 90.9% for extra-adrenal tumors. MIBG sensitivity was 88.5%. In the 263 patients who underwent surgery, the tumor was intra-adrenal in 89.4%, extra-adrenal in 8.5%, intra- and extra-adrenal in 2.1%, and bilateral in 11.0% of patients. Malignancy was reported in 9.9% of cases. Surgery caused remission of hypertension in 59.3%, improvement in 26.8%, and no changes in 13. 9% of patients. In the last group the interval between initial symptoms and diagnosis was significantly longer.



The present study confirms that the clinical presentation of pheochromocytoma is variable and aspecific. Normotension is often present and often the tumor is discovered incidentally. An indication for the routine use of screening methods more sensitive than urinary VMA is strongly suggested. The clonidine test was found to be safe and should be preferred to the glucagon test which has to be restricted to very selected patients. CT and MIBG scintigraphy are almost always successful in localizing the tumor. Reversal of hypertension by surgery seems to depend on an early diagnosis.

title: Brief Communication: Radiographic Contrast Infusion and Catecholamine Release in Patients With Pheochromocytoma
abstract: Contrast media are widely thought to induce hypertensive crisis in patients with pheochromocytoma.  These researchers observed no instances of catecholamine surge or hypertensive crisis in a series of 22 patients with pheochromocytoma undergoing computed tomography with low-osmolar contrast.  The study had limited statistical power to detect differences between case patients and control participants.  Contemporary low-osmolar computed tomography contrast is safe for patients with pheochromocytoma. The Editors Computed tomography (CT) is used to localize pheochromocytoma once it has been biochemically diagnosed. Noncontrast CT has high sensitivity (approximately 90%) in various types of pheochromocytoma, and contrast can increase both the sensitivity and specificity of CT (1). It is commonly believed that the contrast media used for CT can induce hypertensive crisis in patients with pheochromocytoma. Reports of complications (such as hypertensive crisis) are well described in patients who underwent angiography for diagnosis and localization of pheochromocytoma in the 1960s and 1970s (2). However, these invasive procedures used high-osmolar (ionic) contrast agents, which are associated with more adverse events than low-osmolar (nonionic) contrast agents (3). Low-osmolar contrast agents are now used for most invasive and noninvasive radiologic procedures, including contrast-enhanced CT. Since 2003, more than 200 patients with pheochromocytoma have been evaluated with contrast CT at the National Institutes of Health, Bethesda, Maryland. In our experience, there have been no reports of hypertensive crisis after injection of intravenous low-osmolar CT contrast in patients with pheochromocytoma, although we did not routinely record vital signs initially. We report the effect of intravenous administration of low-osmolar contrast during CT on plasma catecholamine release, blood pressure, and heart rate in patients with and without pheochromocytoma, to determine whether it induces catecholamine release that increases blood pressure or heart rate.  The protocol for this study was approved by the institutional review board of the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health. All patients provided written informed consent.  We evaluated plasma catecholamine levels, blood pressure, and heart rate responses in 30 patients who received oral and intravenous low-osmolar contrast (Isovue 300 [Bracco Diagnostics, Princeton, New Jersey; ALTANA Pharma AG, Singen, Germany]), 30 mL at 1.8 to 2.0 mL/h, for whole-body CT at the Warren G. Magnuson Clinical Center, National Institutes of Health. Twenty-two patients had histologically confirmed solitary adrenal or metastatic pheochromocytoma. Eight patients in whom pheochromocytoma had been ruled out served as a control group.   Study flow diagram. CT = computed tomography.  Initial enrollment period. Recommended to the authors to include more patients with solitary adrenal pheochromocytoma. All patients had blood samples obtained through an indwelling forearm venous cannula at baseline (approximately 1 hour before the start of CT with the patient at rest and the intravenous line placed at least 20 minutes before blood draw); prescan (immediately before the start of CT, with the patient instructed to lie on the CT table for 10 minutes before the blood draw and start of CT); and at 5, 10, 15, and 20 minutes after contrast injection. Heart rate and blood pressure were measured at all time points. Patients were supine during all measurements. Contrast was administered intravenously between the prescan and 5-minute postcontrast administration time points. Patients who were receiving antihypertensive medications continued to take these medications. Plasma was analyzed for concentrations of catecholamines, including norepinephrine and epinephrine by high-pressure liquid chromatography, as described elsewhere (4). Statistical Analysis We used the 2-sample t test to compare preinjection and postinjection changes in patients with pheochromocytoma and control participants, comparing the change from the average of the 2 preinjection values with the average of the 4 postinjection values. We also used the 2-sample t test to compare preinjection and postinjection changes in patients with solitary adrenal pheochromocytoma with those in patients with nonadrenal pheochromocytoma. Paired analyses within groups were done by using paired t tests. We used 2-way analysis of variance to test for differences between the patient groups while adjusting for whether the patients were or were not receiving adrenoreceptor blockade medications. For norepinephrine and epinephrine end points, log values were used because the raw values for these 2 variables were heavily skewed. All P values are 2-sided, and a value less than 0.05 was considered statistically significant. Summary values are presented as means. Role of the Funding Source This study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Development, National Institutes of Health. The funding source played a role in the decision to submit the manuscript.  We studied 22 patients with pheochromocytoma (12 women and 10 men; mean age, 46 years [range, 27 to 64 years]) and 8 control participants (4 women and 4 men; mean age, 49 years [range, 35 to 60 years]). The biochemical profile of pheochromocytoma was noradrenergic in 12 patients, adrenergic in 2 patients, mixed noradrenergic and adrenergic in 7 patients, and dopamine-secreting tumor in 1 patient (Table). Values were not available for every variable at each time point (Figure). However, for each variable except epinephrine (28 participants), values were sufficient for all 30 participants to be included in the comparisons of average values obtained before and after contrast administration. Table.  Average norepinephrine and epinephrine levels, heart rate, and blood pressure in patients with pheochromocytoma compared with control participants before and after intravenous administration of computed tomography contrast. Arrows indicate the time of low-osmolar contrast injection. Bars represent 95% CIs. Number of patients with available data shown at each time point; there are no obvious outliers within the data. Compared with preinjection values, epinephrine levels were significantly lower after contrast injection in patients with pheochromocytoma (mean change, 1 log pmol/L [95% CI, 3 to 0 log pmol/L]; P = 0.041). Norepinephrine values did not statistically significantly differ. Systolic blood pressure (mean change, 10 mm Hg [CI, 3 to 16 mm Hg]; P = 0.005) and diastolic blood pressure (mean change, 5 mm Hg [CI, 2 to 9 mm Hg]; P = 0.005) were significantly higher after contrast in the pheochromocytoma group. There was no statistically significant change in heart rate. In the control group, no statistically or clinically significant differences before and after contrast injection were observed in norepinephrine or epinephrine level, systolic or diastolic blood pressure, or heart rate. Average preinjection norepinephrine levels were about 3 times higher in patients with pheochromocytoma than in control participants . However, the average change in norepinephrine levels from before to after contrast injection did not statistically significantly differ between the groups (mean change, 0.0010 log nmol/L [CI, 0.0004 to 0.0024 log nmol/L]; P = 0.148). Average preinjection epinephrine levels were similar in both groups. The between-group difference in average change in epinephrine levels before and after contrast injection was not significant (mean change, 0 log pmol/L [CI, 3 to 2 log pmol/L]; P = 0.69). Preinjection systolic and diastolic blood pressures were similar in patients with pheochromocytoma and control participants. The t tests did not show a significant effect of contrast administration on systolic blood pressure (P = 0.142) but did show a borderline significant effect on diastolic blood pressure (P = 0.045). Average preinjection heart rates were higher in control participants than in patients with pheochromocytoma, although not significantly so. The effect of contrast administration on heart rate also did not significantly differ between the groups (P = 0.69, t test). Nine patients with pheochromocytoma and 2 control participants were taking -blockers, and 9 patients with pheochromocytoma and 3 control participants were taking -blockers. Norepinephrine and epinephrine levels, systolic and diastolic blood pressure, and heart rate did not significantly differ before and after contrast administration between patients with pheochromocytoma and control participants after adjustment for use of - and -blockers. The between-group differences in diastolic blood pressure became nonstatistically significant after adjustment for -blocker use (P = 0.058) or -blocker use (P = 0.069). Changes in norepinephrine and epinephrine levels, systolic and diastolic blood pressure, and heart rate did not statistically significantly differ before and after contrast injection in patients with solitary adrenal pheochromocytoma and those with nonadrenal pheochromocytoma.  We found little evidence that oral or intravenous administration of low-osmolar contrast leads to catecholamine release or catecholamine-induced increases in blood pressure or heart rate in patients with pheochromocytoma, findings that support our clinical observations that intravenous low-osmolar CT contrast does not induce hypertensive crisis in pheochromocytoma patients. A few patients had clinically significant increases in systolic and diastolic blood pressure and moderate increases in heart rate; however, these results were incongruent with their respective change in catechola

title: Extra-adrenal pheochromocytoma: Diagnosis and management
abstract: Extra-adrenal pheochromocytomas (EAPs) may arise in any portion of the paraganglion system, though they most commonly occur below the diaphragm, frequently in the organ of Zuckerkandl. EAPs probably represent at least 15% of adult and 30% of childhood phenochromocytomas, as opposed to the traditional teaching that 10% of all pheochromocytomas are at extra-adrenal sites. They may be malignant in up to 40% of the cases, though conflicting data add to the uncertainty of this point. Patients with EAPs may present with headache, palpitations, sweating, or hypertension. A small percent of patients may also be asymptomatic at presentation due to nonfunctional tumors. The diagnosis is confirmed by demonstrating elevated blood and urine levels of catecholamines and their metabolites. Imaging studies to evaluate for EAPs include CT, MRI, and 131I-labelled metaiodobenzylguanidine scintigraphy. Preoperative pharmacologic preparation, attentive intraoperative monitoring, and aggressive surgical therapy have important roles in achieving successful outcomes. Recent reports suggest that a laparoscopic approach, along with intraoperative ultrasound, can safely remove these tumors. EAPs recur and metastasize more often than their adrenal counterparts, making lifelong follow-up essential.

title: Detection of metastatic lesions from malignant pheochromocytoma and paraganglioma with diffusion-weighted magnetic resonance imaging: comparison with 18F-FDG positron emission tomography and 123I-MIBG scintigraphy
abstract: ObjectiveTo investigate the diagnostic features of whole-body diffusion-weighted magnetic resonance imaging (DWI) as compared with 2-[18F]-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) and 123I-meta-iodo-benzyl guanidine scintigraphy (MIBG) on metastatic lesions of patients with malignant pheochromocytoma or paraganglioma.MethodsWe prospectively studied 11 patients with histologically confirmed pheochromocytoma/paraganglioma and possible metastatic lesions. FDG-PET, MIBG, and DWI examinations were performed within 1 week, and the images were visually interpreted. Abnormal positive uptake either on MIBG or on FDG-PET was considered as metastases. Abnormal high signal intensities on DWI were considered as metastases using conventional T1-and T2-weighted images as reference.ResultsFDG-PET and DWI demonstrated metastatic lesions in all 11 patients, but MIBG showed no metastatic lesions in two patients. The numbers of lymph node metastases depicted on FDG-PET, MIBG, and DWI were 19, 6, and 39; bone metastases were 50, 49, and 60; liver metastases were 9, 9, and 15; lung metastases were 5, 7, and 5, respectively. MIBG failed to demonstrate many metastatic lesions, which were demonstrated on FDG-PET or DWI, although two mediastinal lymph node metastases, three lung metastases, and six bone metastases, which were not seen on DWI, were clearly demonstrated on MIBG. DWI showed 15 liver metastases, but 6 of them were not seen on FDG-PET or MIBG.ConclusionsDWI may be particularly advantageous in depicting lymph node and liver metastases and may have a higher rate of detecting metastatic lesions when compared with MIBG or FDG-PET. The limitations of DWI were possible false-positive finding, and probable lower detectability of mediastinal lymph node and lung metastasis.

title: Localization of pheochromocytoma: MIBG [correction of MIGB], CT, and MRI correlation.
abstract: Nineteen patients (8 M, 11F) ranging in age from 15 - 67 yr old (mean = 39 yr) with clinically diagnosed pheochromocytomas were prospectively evaluated with 131I metaiodobenzyl-guanidine (MIBG) scintigraphy (n = 19), computed tomography (CT) (n = 19), and magnetic resonance imaging (MRI) (n = 17) in order to determine their relative diagnostic efficacy. Pathologic confirmation was obtained in all 19 patients: 13 intraadrenal and six extraadrenal with metastases in five (Table 1). All three imaging modalities were in agreement in 11 of 14 completed examinations (79%). MIBG and CT agreed in 16 of the 19 patients in whom both were performed (84%). MIBG/MR and CT/MR results were concordant in 12 of 14 (86%) and 13 of 14 (93%) jointly completed examinations, respectively. There was one false-negative (FN) MIBG scan, two FN CT scans, and one FN MR scan. MIBG, CT, and MRI are complementary procedures with MIBG providing more specific functional information and the latter two superior anatomic detail. MIBG scintigraphy is recommended as the initial localizing study of choice (especially for the detection of extraadrenal disease and postoperative recurrence), as a guide for CT and/or MR and specific functional confirmation of their findings. Although MRI is capable of imaging in multiple planes (without exposure to ionizing radiation or the need for i.v. contrast material) with superior contrast compared to CT, it is expensive and has poor patient cooperation. However, it may be capable of differentiating pheochromocytomas from other adrenal masses on the basis of signal characterization.

title: The Utility of Metaiodobenzylguanidine (MIBG) Scintigraphy in Patients with Pheochromocytoma
abstract: BackgroundRadiolabeled metaiodobenzylguanidine scintigraphy (MIBG) can be used to image pheochromocytomas. While cross-sectional imaging techniques such as computed tomography (CT) or magnetic resonance imaging (MRI) usually localize the tumor, MIBG is often obtained to rule out multifocal and metastatic disease, and to corroborate anatomic imaging with functional data. We questioned the utility of MIBG in the diagnosis and management of pheochromocytoma.MethodsAll patients who received MIBG at one academic center from 1999 to 2004 were identified. For the subset of patients who received MIBG in the work-up of possible pheochromocytoma, the following data were reviewed: demographics, symptoms, results of biochemical and imaging studies, histopathological diagnosis, and management. total of 60 patients received MIBG, including 27 patients for the evaluation of a possible pheochromocytoma. Biochemical testing was performed in all patients. Fourteen patients received MIBG despite normal biochemistry and an absence of risk factors such as a hereditary syndrome or prior history of pheochromocytoma. None of these 14 low-risk patients with negative biochemistry had a final diagnosis of pheochromocytoma. In the ten patients with pheochromocytoma, all tumors were localized by CT and/or MRI. Importantly, MIBG did not identify any foci of disease not seen on cross sectional imaging, and MIBG did not alter the surgical management of any patient in this series.ConclusionsIn patients with clinical findings suggestive of pheochromocytoma, biochemical testing should be used to confirm the diagnosis, and cross-sectional imaging is sufficient for tumor localization. In the absence of hereditary disease or a past history of pheochromocytoma, MIBG does not alter the treatment plan and therefore should not be routinely performed. Instead, MIBG should be used selectively, such as for the rare patient with a biochemical diagnosis of pheochromocytoma and no tumor seen on exhaustive anatomical imaging.

title: Iodine-131-metaiodobenzylguanidine scintigraphy in preoperative and postoperative evaluation of paragangliomas: comparison with CT and MRI.
abstract: Iodine-131-metaiodobenzylguanidine (MIBG) scintigraphy, transmission computed tomography and magnetic resonance imaging were used to evaluate 36 patients with clinically suspected functioning paragangliomas. The patients were divided into two groups. In Group 1 (n = 21), studied before surgery, patients mainly had benign adrenal disease. In Group 2 (n = 15), studied after surgery, patients frequently had malignant or extra-adrenal tumors. In Group 1, transmission computed tomography and magnetic resonance imaging were more sensitive (100% for both) than MIBG scintigraphy (82%), which, however, was the most specific (100%). In Group 2, MIBG scintigraphy and magnetic resonance imaging were more sensitive (83% for both) than transmission computed tomography (75%), but MIBG was again the most specific (100%). Thus, all three were complementary modalities for localizing paragangliomas both preoperatively and postoperatively. MIBG imaging is indicated for both groups but it is especially recommended for postsurgical patients with recurrence because the disease is often malignant or extra-adrenal.

title: Routine preoperative 123I-MIBG scintigraphy for patients with phaeochromocytoma is not necessary
abstract: BackgroundFunctional imaging using 123I-meta-iodo-benzyl-guanetidine (MIBG) scintigraphy has alleged 100% specificity for phaeochromocytoma (PHAEO). Its benefit in patients with biochemical diagnosis of PHAEO is arguable when cross-sectional radiology can demonstrate the side–size of the adrenal tumours.Materials and methodsThis is a retrospective review of clinical notes of patients undergoing adrenalectomy for PHAEO in a University centre.ResultsBetween January 2000 and December 2007, adrenalectomy for PHAEO was performed on 66 patients (28 M and 38 F, aged 24–82 years). Diagnosis was demonstrated by raised 24-h urine catecholamines (n = 14) or metanephrines (n = 52). The side and size of adrenal tumours were demonstrated on computed tomography (n = 58) and/or magnetic resonance imaging (n = 20) scans. MIBG scans were performed in 38 patients. Four of these patients were found to have non-adrenal pathology (haemangioblastomas, haemangioma, a bronchogenic cyst and an angiomyolipoma); hence, the positive predictive value of MIBG scan was 90%. In a further five patients, MIBG raised the suspicion of local metastatic disease but this was not confirmed on operative findings and no recurrence was detected in these patients during 6–92-month follow-up. This led to an overall rate of false-positive rate of 23%.ConclusionMIBG scintigraphy adds little to the routine preoperative management of patients with suspected PHAEO. Its use should be limited to the small minority of patients with negative cross-sectional imaging and those with recurrent or metastatic disease.

title: Iodine-123-MIBG SPECT versus planar imaging in children with neural crest tumors.
abstract: Iodine-123-metaiodobenzylguanidine (MIBG) SPECT was compared with 123I-MIBG planar imaging in 35 studies of 25 children with neural crest tumors.



Iodine-123-MIBG (0.070-0.140 mCi/kg intravenously) was followed at 24 hr by wholebody planar imaging and triple-detector, high-resolution thoraco-abdominal SPECT. At 48 hr, thoracoabdominal planar imaging was performed whenever a high-tissue background or gut activity interfered with the interpretation of the 24-hr planar images. SPECT views included a cine loop presentation of multiple volume-rendered projections. Two reviewers enumerated the number of abnormal sites on the planar and SPECT studies and rated the certainty of interpretation for each study on a scale from 0.1 (low certainty) to 1.0 (high).



Abnormal uptake was noted on planar or SPECT imaging in 13 studies (seven patients). The average number of abnormal sites detected per study for all 35 studies was 2.7 for planar imaging and 2.9 for SPECT (p = not significant) (and 7.2 and 8.4 for planar and SPECT, respectively, for the 13 abnormal studies.) The certainty ratings for all 35 studies were 0.74 for planar studies, 0.82 for SPECT (p = 0.05, chi-square, compared with planar) and 0.86 for planar and SPECT combined (p = 0.01 compared with planar alone). On volume-rendered images, gut activity was seen as diffuse and/or linear intraluminal activity.



When 123I-MIBG SPECT is used, the number of lesions detected is not increased, but there is a significant improvement in the certainty of interpretation over planar imaging.

title: Octreotide scintigraphy and catecholamine response to an octreotide challenge in malignant phaeochromocytoma
abstract: Octreotide scintigraphy has been reported to visualize chromaffine tumours. This study in patients with malignant phaeochromocytoma was designed to assess octreotide in comparison with standard m‐iodobenzylguanidine (MIBG) scintigraphy and to study functional activity of somatostatin receptors. Finally, two cases of octreotide treatment are reported.

title: Comparison of radiolabeled octreotide and meta-iodobenzylguanidine (MIBG) scintigraphy in malignant pheochromocytoma.
abstract: The results of in vivo somatostatin scintigraphy were correlated with those of MIBG from 14 patients, aged 22-66 yr, with metastatic pheochromocytoma (10 patients), malignant paraganglioma (3 patients) and metastatic ganglioneuroblastoma (1 patient). Twelve patients had elevated catecholamine excretion. A dynamic study and serial whole-body scans (4-48 hr) were obtained after injection of 130-187 MBq of 111In-DTPA-Phe-1-octreotide. When indicated, SPECT imaging was done. The results were compared to MIBG scans obtained after a diagnostic or a therapeutic dose.



Three patients with more than 20 tumor sites on MIBG scans had only 1-9 sites on 111In-octreotide scintigraphy. Two patients had no MIBG uptake but one had lung uptake on octreotide scintigraphy. In the other 9 patients with a total of 41 foci of MIBG uptake, 33 sites of 111In-octreotide uptake are found. All positive images with octreotide scintigraphy were seen at or before 4 hr, but the contrast improved at 24 hr. Uptake intensity was lower with 111In-octreotide than MIBG and the number of tumor sites was higher with MIBG. However, seven foci were positive only on octreotide scintigraphy and six of them could not be confirmed by other imaging modalities.



Use of octreotide to identify somatostatin receptors seems promising, especially when results from MIBG scans are negative. Moreover octreotide images could aid in determining a treatment regimen as well as establishing the extent of disease and prognosis.

title: Comparison of somatostatin analog and meta-iodobenzylguanidine radionuclides in the diagnosis and localization of advanced neuroendocrine tumors.
abstract: A comparison has been made of [(123)I]meta-iodobenzylguanidine ([(123)I]MIBG) and [(111)In]pentetreotide scintigraphy in 54 patients with a variety of neuroendocrine tumors of whom 46 patients had metastatic disease.

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

title: Superiority of fluorodeoxyglucose positron emission tomography to other functional imaging techniques in the evaluation of metastatic SDHB-associated pheochromocytoma and paraganglioma.
abstract: Germline mutations of the gene encoding subunit B of the mitochondrial enzyme succinate dehydrogenase (SDHB) predispose to malignant paraganglioma (PGL). Timely and accurate localization of these aggressive tumors is critical for guiding optimal treatment. Our aim is to evaluate the performance of functional imaging modalities in the detection of metastatic lesions of SDHB-associated PGL.



Sensitivities for the detection of metastases were compared between [18F]fluorodopamine ([18F]FDA) and [18F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET), iodine-123- (123I) and iodine-131 (131I) -metaiodobenzylguanidine (MIBG), 111In-pentetreotide, and Tc-99m-methylene diphosphonate bone scintigraphy in 30 patients with SDHB-associated PGL. Computed tomography (CT) and magnetic resonance imaging (MRI) served as standards of reference.



Twenty-nine of 30 patients had metastatic lesions. In two patients, obvious metastatic lesions on functional imaging were missed by CT and MRI. Sensitivity according to patient/body region was 80%/65% for 123I-MIBG and 88%/70% for [18F]FDA-PET. False-negative results on 123I-MIBG scintigraphy and/or [18F]FDA-PET were not predicted by genotype or biochemical phenotype. [18F]FDG-PET yielded a by patient/by body region sensitivity of 100%/97%. At least 90% of regions that were false negative on 123I-MIBG scintigraphy or [18F]FDA-PET were detected by [18F]FDG-PET. In two patients, 111In-pentetreotide scintigraphy detected liver lesions that were negative on other functional imaging modalities. Sensitivities were similar before and after chemotherapy or 131I-MIBG treatment, except for a trend toward lower post- (60%/41%) versus pretreatment (80%/65%) sensitivity of 123I-MIBG scintigraphy.



With a sensitivity approaching 100%, [18F]FDG-PET is the preferred functional imaging modality for staging and treatment monitoring of SDHB-related metastatic PGL.

title: Treatment planning for 131I-mIBG radiotherapy of neural crest tumours using 124I-mIBG positron emission tomography.
abstract: Patients designated to receive 131I-meta-iodobenzylguanadine (mIBG) for the treatment of neural crest tumours have been scanned with 124I-mIBG using the MUP-PET positron camera. Uptake was detected in tumour sites in lung, liver and abdomen. The tomographic images produced have allowed estimates to be made of the concentration of mIBG in both tumour and normal tissue. From these data it is possible to predict the radiation doses that would be achieved using therapy levels (up to 11 GBq) of 131I-mIBG. The levels of tumour uptake are between 0.5 and 2.0 kBq/g indicating that the radiation doses to tumour would be in the range 3 Gy to 7.5 Gy.

title: An efficient batch preparation of high specific activity.
abstract: The increasing demand for radiolabeled metaiodobenzylguanidine (mIBG) prompted the need to obtain the radiopharmaceutical by a reliable, routine and simple synthetic method for batch production. The production of mIBG labeled with either 123I or 124I has been optimized by modifying literature methods that involve solid-state exchange reaction on "cold" mIBG facilitated by ammonium sulfate. The radiochemical yield and purity of radioiodinated mIBG generally exceeded 80 and 98%, respectively, with specific activity of > 50 mCi/mg.

title: A Novel Recombinant Vaccinia Virus Expressing the Human Norepinephrine Transporter Retains Oncolytic Potential and Facilitates Deep-Tissue Imaging
abstract: Noninvasive and repetitive monitoring of a virus in target tissues and/or specific organs of the body is highly desirable for the development of safe and efficient cancer virotherapeutics. We have previously shown that the oncolytic vaccinia virus GLV-1h68 can target and eradicate human tumors in mice and that its therapeutic effects can be monitored by using optical imaging. Here, we report on the development of a derivative of GLV-1h68, a novel recombinant vaccinia virus (VACV) GLV-1h99, which was constructed to carry the human norepinephrine transporter gene (hNET) under the VACV synthetic early promoter placed at the F14.5L locus for deep-tissue imaging. The hNET protein was expressed at high levels on the membranes of cells infected with this virus. Expression of the hNET protein did not negatively affect virus replication, cytolytic activity in cell culture, or in vivo virotherpeutic efficacy. GLV-1h99-mediated expression of the hNET protein in infected cells resulted in specific uptake of the radiotracer (131I)-meta-iodobenzylguanidine (MIBG). In mice, GLV-1h99-infected tumors were readily imaged by (124I)-MIBG positron emission tomography. To our knowledge, GLV-1h99 is the first oncolytic virus expressing the hNET protein that can efficiently eliminate tumors and simultaneously allow deep-tissue imaging of infected tumors.

title: Pheochromocytomas: imaging with 2-[fluorine-18]fluoro-2-deoxy-D-glucose PET.
abstract: To assess the sensitivity of positron emission tomography (PET) with 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) in pheochromocytomas and, secondarily, to compare images obtained with FDG PET to those obtained with metaiodobenzylguanidine (MIBG) scintigraphy.



Twenty-nine patients with one or more known or subsequently proved pheochromocytomas underwent FDG PET (35 scans) and MIBG scintigraphy (35 scans). Tumor uptake of FDG was quantified on positive PET scans.



Tumor uptake of FDG was detected in 22 of 29 patients. Most benign (seven of 12 patients) and most malignant (15 of 17 patients) pheochromocytomas and their metastases avidly concentrated FDG. In four patients whose pheochromocytomas failed to accumulate MIBG, uptake of FDG in the tumors was intense. For the majority of the 16 patients whose tumors concentrated both agents, however, ratings for MIBG images compared to FDG PET images for delineation of the tumor in comparison to background and normal organ accumulation were superior for nine patients (56%) and as good or better for 14 (88%).



Most pheochromocytomas accumulate FDG. Uptake is found in a greater percentage of malignant than benign pheochromocytomas. FDG PET is especially useful in defining the distribution of those pheochromocytomas that fail to concentrate MIBG.

title: Superiority of 6-[18F]-fluorodopamine positron emission tomography versus [131I]-metaiodobenzylguanidine scintigraphy in the localization of metastatic pheochromocytoma.
abstract: 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.

title: Pheochromocytomas that do not accumulate metaiodobenzylguanidine: localization with PET and administration of FDG.
abstract: Many imaging methods can be used to detect pheochromocytoma, but some tumors are not detected with conventional modalities. To explore the possible usefulness of positron emission tomography (PET) after administration of 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (FDG) to localize pheochromocytoma in patients with false-negative scintigrams obtained after administration of metaiodobenzylguanidine (MIBG), FDG was administered and PET was performed in two adult patients with pheochromocytomas that had never been localized despite administration of MIBG. In both patients, images were obtained dynamically for 50 minutes; then a limited truncal sequence was performed. PET enabled correct localization of the tumors. In patient 1, a tumor that had not been detected for 21 years was localized in the middle mediastinum; in patient 2, a pheochromocytoma was detected in the right adrenal gland. PET performed after administration of FDG may be useful for localization of pheochromocytomas that do not accumulate MIBG.

title: 6-[18F]Fluorodopamine Positron Emission Tomographic (PET) Scanning for Diagnostic Localization of Pheochromocytoma
abstract: 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 131I-metaiodobenzylguanidine scintigraphy have limited sensitivity. Here we report initial results using 6-[18F]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-[18F]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-[18F]fluorodopamine PET scans that identified the tumors. All 8 patients with metastatic pheochromocytoma had extra-adrenal sites of 6-[18F]fluorodopamine-derived activity. Of the 11 patients with normal plasma levels of metanephrines, 9 had negative 6-[18F]fluorodopamine PET scans, 1 had extra-adrenal foci of 6-[18F]fluorodopamine-derived activity, and 1 had symmetric uptake of 6-[18F]fluorodopamine in the region of the adrenal glands. In patients with known disease, 6-[18F]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-[18F]fluorodopamine PET scans are consistently negative. These findings justify a clinical trial of 6-[18F]fluorodopamine PET scanning as a diagnostic tool.

title: Usefulness of Standardized Uptake Values for Distinguishing Adrenal Glands with Pheochromocytoma from Normal Adrenal Glands by Use of 6-18F-Fluorodopamine PET
abstract: 6-18F-Fluorodopamine (18F-FDA) PET is a highly sensitive tool for the localization of pheochromocytoma (PHEO). The aim of this study was to establish cutoff values for pathologic and physiologic adrenal gland tracer uptake.  18F-FDA PET with CT coregistration was performed in 14 patients (10 men and 4 women; age [mean ± SD], 42.9 ± 13.3 y) with unilateral adrenal gland PHEO and in 13 control subjects (5 men and 8 women; age, 51.7 ± 12.5 y) without PHEO. Standardized uptake values (SUVs) were compared between adrenal glands with PHEO and normal left adrenal glands in control subjects.  18F-FDA accumulation was observed in all adrenal glands with PHEO and in 6 of 13 control adrenal glands (P = 0.02). The SUV was higher in adrenal glands with PHEO (mean ± SD, 16.1 ± 6.1) than in 18F-FDA–positive control adrenal glands (7.7 ± 1.4) (P = 0.005). SUV cutoffs for distinguishing between adrenal glands with PHEO and normal adrenal glands were 7.3 (100% sensitivity) and 10.1 (100% specificity).  The SUVs of adrenal foci on 18F-FDA PET facilitate the distinction between adrenal glands with PHEO and normal adrenal glands.

title: Discordant localization of 2-[18F]-fluoro-2-deoxy-D-glucose in 6-[18F]-fluorodopamine- and [123I]-metaiodobenzylguanidine-negative metastatic pheochromocytoma sites
abstract: BackgroundAlthough 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, [131I]- or [123I]-metaiodobenzylguanidine ([131I]- or [123I]-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. MethodsFive 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 [123I]-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. ResultsAll five patients had [123I]-MIBG scans that grossly underestimated the extent of disease when compared with conventional CT and MRI. All lesions seen on [123I]-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 [123I]-MIBG or [18F]-DA scans. ConclusionsWhen [123I]-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.

title: Pheochromocytomas: detection with 18F DOPA whole body PET--initial results..
abstract: 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.

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

title: Neuroendocrine tumors and somatostatin: imaging techniques.
abstract: Tumors and metastases bearing the somatostatin receptor subtypes 2 (SSTR2) or SSTR5 can be visualized in vivo after injection of radiolabeled octapeptide somatostatin analogs like 111In-pentetreotide. The sensitivity of 111In-pentetreotide scintigraphy for the detection of carcinoid tumors is 86-95%. The sensitivity of 111In-pentetreotide scintigraphy for the detection of gastrinomas, vasoactive intestinal polypeptide-secreting tumors, and glucagonomas as well as clinically non-functioning lesions is 75-100%. However, for insulinoma this is 50-60%. 111In-pentetreotide scintigraphy generally has a lower detection rate for benign pheochromocytomas than 123I-MIBG scintigraphy, but it can have a complementary role for the staging of malignant pheochromocytomas. It can also be used for the detection of extra-adrenal pheochromocytomas and paragangliomas. Most GH- and TSH-secreting pituitary adenomas can be visualized using 111In-pentetreotide. 111In-pentetreotide scintigraphy is negative in microprolactinomas and ACTH-secreting pituitary microadenomas. 111In-pentetreotide scintigraphy has been successful for the localization of extra-pituitary ACTH-secreting tumors and their metastases, and especially for occult tumors. A large variety of lesions in and around the pituitary region express somatostatin receptors and, therefore, can be visualized by 111In-pentetreotide scintigraphy.

title: Diagnostic applications of radiolabeled peptides in nuclear endocrinology.
abstract: Regulatory peptides are small, readily diffusable and potent natural substances with a wide spectrum of receptor-mediated actions in humans. High affinity receptors for these peptides are (over-) expressed in many neoplasms, and these receptors may represent, therefore, new molecular targets for cancer diagnosis and therapy. This review intends to give an overview of the peptide-based radiopharmaceuticals which are presently already commercially available or which are in advanced stages of their clinical testing so that their broader availability is anticipated soon. Physiologically, these peptides bind to and act through G protein-coupled receptors in the cell membrane. Historically, somatostatin analogs are the first class of receptor binding peptides having gained clinical application. 111In-DTPA-[D-Phe1]-octreotide is the first and only radiopeptide which has obtained regulatory approval in Europe and the United States to date. Extensive clinical studies involving several thousands of patients have shown that the major clinical application of somatostatin receptor scintigraphy is the detection and the staging of gastroenteropancreatic neuroendocrine tumors (carcinoids). In these tumors, octreotide scintigraphy is superior to any other staging method. However, its sensitivity and accuracy in other, more frequent neoplasms is limited. Radiolabeled vasoactive intestinal peptide (VIP) has been shown to visualize the majority of gastrointestinal adenocarcinomas, as well as some neuroendocrine tumors, including insulinomas (the latter being often missed by somatostatin receptor scintigraphy). Due to the outstanding diagnostic accuracy of the pentagastrin test in detecting the presence, persistence, or recurrence of medullary thyroid cancer (MTC), we postulated the expression of the corresponding [i.e., cholecystokinin (CCK-)-B] receptor type in human MTC. This receptor is also widely expressed on human small-cell lung cancer. Indeed, 111In-labeled DTPA derivatives of gastrin showed excellent targeting of CCK-B receptor expressing tissues in animals and patients. A variety of further peptide-based radioligands is currently under development. Summarizing, radiolabeled regulatory peptides have opened new horizons in nuclear oncology for diagnosis (and potential internal radionuclide therapy). Further work will probably reveal a multitude of novel potentially clinically useful peptide-based radioligands.

title: Peptide Receptor Radionuclide Therapy with radiolabelled somatostatin analogues in patients with somatostatin receptor positive tumours
abstract: Peptide Receptor Radionuclide Therapy (PRRT) with radiolabelled somatostatin analogues is a promising treatment option for patients with inoperable or metastasised neuroendocrine tumours. Symptomatic improvement may occur with all of the various 111In, 90Y, or 177Lu-labelled somatostatin analogues that have been used. Since tumour size reduction was seldom achieved with 111Indium labelled somatostatin analogues, radiolabelled somatostatin analogues with beta-emitting isotopes like 90Y and 177Lu were developed. Reported anti-tumour effects of [90Y-DOTA0,Tyr3]octreotide vary considerably between various studies: Tumour regression of 50% or more was achieved in 9 to 33% (mean 22%). With [177Lu-DOTA0,Tyr3]octreotate treatments, tumour regression of 50% or more was achieved in 28% of patients and tumour regression of 25 to 50% in 19% of patients, stable disease was demonstrated in 35% and progressive disease in 18%. Predictive factors for tumour remission were high tumour uptake on somatostatin receptor scintigraphy and limited amount of liver metastases. The side-effects of PRRT are few and mostly mild, certainly when using renal protective agents: Serious side-effects like myelodysplastic syndrome or renal failure are rare. The median duration of the therapy response for [90Y-DOTA0,Tyr3]octreotide and [177Lu-DOTA0,Tyr3]octreotate is 30 months and more than 36 months respectively. Lastly, quality of life improves significantly after treatment with [177Lu-DOTA0,Tyr3]octreotate. These data compare favourably with the limited number of alternative treatment approaches, like chemotherapy. If more widespread use of PRRT is possible, such therapy might become the therapy of first choice in patients with metastasised or inoperable gastroenteropancreatic neuroendocrine tumours. Also the role in somatostatin receptor expressing non-GEP tumours, like metastasised paraganglioma/pheochromocytoma and non-radioiodine-avid differentiated thyroid carcinoma might become more important.

title: Comparison of 18F-fluoro-L-DOPA, 18F-fluoro-deoxyglucose, and 18F-fluorodopamine PET and 123I-MIBG scintigraphy in the localization of pheochromocytoma and paraganglioma.
abstract: Besides (123)I-metaiodobenzylguanidine (MIBG), positron emission tomography (PET) agents are available for the localization of paraganglioma (PGL), including (18)F-3,4-dihydroxyphenylalanine (DOPA), (18)F-fluoro-2-deoxy-D-glucose ((18)F-FDG), and (18)F-fluorodopamine ((18)F-FDA).



The objective of the study was to establish the optimal approach to the functional imaging of PGL and examine the link between genotype-specific tumor biology and imaging.



This was a prospective observational study.



There were no interventions.



Fifty-two patients (28 males, 24 females, aged 46.8 +/- 14.2 yr): 20 with nonmetastatic PGL (11 adrenal), 28 with metastatic PGL (13 adrenal), and four in whom PGL was ruled out; 22 PGLs were of the succinate dehydrogenase subunit B (SDHB) genotype.



Sensitivity of (18)F-DOPA, (18)F-FDG, and (18)F-FDA PET, (123)I-MIBG scintigraphy, computed tomography (CT), and magnetic resonance imaging (MRI) for the localization of PGL were measured.



Sensitivities for localizing nonmetastatic PGL were 100% for CT and/or MRI, 81% for (18)F-DOPA PET, 88% for (18)F-FDG PET/CT, 78% for (18)F-FDA PET/CT, and 78% for (123)I-MIBG scintigraphy. For metastatic PGL, sensitivity in reference to CT/MRI was 45% for (18)F-DOPA PET, 74% for (18)F-FDG PET/CT, 76% for (18)F-FDA PET/CT, and 57% for (123)I-MIBG scintigraphy. In patients with SDHB metastatic PGL, (18)F-FDA and (18)F-FDG have a higher sensitivity (82 and 83%) than (123)I-MIBG (57%) and (18)F-DOPA (20%).



(18)F-FDA PET/CT is the preferred technique for the localization of the primary PGL and to rule out metastases. Second best, equal alternatives are (18)F-DOPA PET and (123)I-MIBG scintigraphy. For patients with known metastatic PGL, we recommend (18)F-FDA PET in patients with an unknown genotype, (18)F-FDG or (18)F-FDA PET in SDHB mutation carriers, and (18)F-DOPA or (18)F-FDA PET in non-SDHB patients.

title: 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.