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11C-hydroxy-ephedrine-PET/CT in the Diagnosis of Pheochromocytoma and Paraganglioma.

ABSTRACT: Pheochromocytomas (PCC) and paragangliomas (PGL) may be difficult to diagnose because of vague and uncharacteristic symptoms and equivocal biochemical and radiological findings. This was a retrospective cohort study in 102 patients undergoing 11C-hydroxy-ephedrine (11C-HED)-PET/CT because of symptoms and/or biochemistry suspicious for PCC/PGL and/or with radiologically equivocal adrenal incidentalomas. Correlations utilized CT/MRI, clinical, biochemical, surgical, histopathological and follow-up data. 11C-HED-PET/CT correctly identified 19 patients with PCC and six with PGL, missed one PCC, attained one false positive result (nodular hyperplasia) and correctly excluded PCC/PGL in 75 patients. Sensitivity, specificity, positive and negative predictive values of 11C-HED-PET/CT for PCC/PGL diagnosis was 96%, 99%, 96% and 99%, respectively. In 41 patients who underwent surgical resection and for whom correlation to histopathology was available, the corresponding figures were 96%, 93%, 96% and 93%, respectively. Tumor 11C-HED-uptake measurements (standardized uptake value, tumor-to-normal-adrenal ratio) were unrelated to symptoms of catecholamine excess (p > 0.05) and to systolic blood pressure (p > 0.05). In PCC/PGL patients, norepinephrine and systolic blood pressure increased in parallel (R2 = 0.22, p = 0.016). 11C-HED-PET/CT was found to be an accurate tool to diagnose and rule out PCC/PGL in complex clinical scenarios and for the characterization of equivocal adrenal incidentalomas. PET measurements of tumor 11C-HED uptake were not helpful for tumor characterization.

SUBMITTER: Vyakaranam AR

PROVIDER: S-EPMC6627429 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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11C-hydroxy-ephedrine-PET/CT in the Diagnosis of Pheochromocytoma and Paraganglioma.

Vyakaranam Achyut Ram AR Crona Joakim J Norlén Olov O Hellman Per P Sundin Anders A

Cancers 20190619 6

Pheochromocytomas (PCC) and paragangliomas (PGL) may be difficult to diagnose because of vague and uncharacteristic symptoms and equivocal biochemical and radiological findings. This was a retrospective cohort study in 102 patients undergoing 11C-hydroxy-ephedrine (11C-HED)-PET/CT because of symptoms and/or biochemistry suspicious for PCC/PGL and/or with radiologically equivocal adrenal incidentalomas. Correlations utilized CT/MRI, clinical, biochemical, surgical, histopath ...[more]

PMID: 31248124

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Project description:Although pediatric pheochromocytomas and paragangliomas (PPGLs) are rare, they have important differences compared to those in adults. Unfortunately, without timely diagnosis and management, these tumors have a potentially devastating impact on pediatric patients. Pediatric PPGLs are more often extra-adrenal, multifocal/metastatic, and recurrent, likely due to these tumors being more commonly due to a genetic predisposition than in adults. This genetic risk results in disease manifestations at an earlier age giving these tumors time to advance before detection. In spite of these problematic features, advances in the molecular and biochemical characterization of PPGLs have heralded an age of increasingly personalized medicine. An understanding of the genetic basis for an individual patient's tumor provides insight into its natural history and can guide clinicians in management of this challenging disease. In pediatric PPGLs, mutations in genes related to pseudohypoxia are most commonly seen, including the von Hippel-Lindau gene (VHL) and succinate dehydrogenase subunit (SDHx) genes, with the highest risk for metastatic disease associated with variants in SDHB and SDHA. Such pathogenic variants are associated with a noradrenergic biochemical phenotype with resultant sustained catecholamine release and therefore persistent symptoms. This is in contrast to paroxysmal symptoms (e.g., episodic hypertension, palpitations, and diaphoresis/flushing) as seen in the adrenergic, or epinephrine-predominant, biochemical phenotype (due to episodic catecholamine release) that is commonly observed in adults. Additionally, PPGLs in children more often present with signs and symptoms of catecholamine excess. Therefore, children, adolescents, and young adults present differently from older adults (e.g., the prototypical presentation of palpitations, perspiration, and pounding headaches in the setting of an isolated adrenal mass). These presentations are a direct result of genetic determinants and highlight the need for pediatricians to recognize these differences in order to expedite appropriate evaluations, including genetic testing. Identification and familiarity with causative genes inform surveillance and treatment strategies to improve outcomes in pediatric patients with PPGL.

Project description:BackgroundPheochromocytomas (PCCs) and paragangliomas (PGLs) are neuroendocrine tumors that are mostly benign. Metastatic disease does occur in about 10% of cases of PCC and up to 25% of PGL, and for these patients no effective therapies are available. Patients with mutations in the succinate dehydrogenase subunit B (SDHB) gene tend to have metastatic disease. We hypothesized that a down-regulation in the active succinate dehydrogenase B subunit should result in notable changes in cellular metabolic profile and could present a vulnerability point for successful pharmacological targeting.MethodsMetabolomic analysis was performed on human hPheo1 cells and shRNA SDHB knockdown hPheo1 (hPheo1 SDHB KD) cells. Additional analysis of 115 human fresh frozen samples was conducted. In vitro studies using N1,N11-diethylnorspermine (DENSPM) and N1,N12- diethylspermine (DESPM) treatments were carried out. DENSPM efficacy was assessed in human cell line derived mouse xenografts.ResultsComponents of the polyamine pathway were elevated in hPheo1 SDHB KD cells compared to wild-type cells. A similar observation was noted in SDHx PCC/PGLs tissues compared to their non-mutated counterparts. Specifically, spermidine, and spermine were significantly elevated in SDHx-mutated PCC/PGLs, with a similar trend in hPheo1 SDHB KD cells. Polyamine pathway inhibitors DENSPM and DESPM effectively inhibited growth of hPheo1 cells in vitro as well in mouse xenografts.ConclusionsThis study demonstrates overactive polyamine pathway in PCC/PGL with SDHB mutations. Treatment with polyamine pathway inhibitors significantly inhibited hPheo1 cell growth and led to growth suppression in xenograft mice treated with DENSPM. These studies strongly implicate the polyamine pathway in PCC/PGL pathophysiology and provide new foundation for exploring the role for polyamine analogue inhibitors in treating metastatic PCC/PGL. PRéCIS: Cell line metabolomics on hPheo1 cells and PCC/PGL tumor tissue indicate that the polyamine pathway is activated. Polyamine inhibitors in vitro and in vivo demonstrate that polyamine inhibitors are promising for malignant PCC/PGL treatment. However, further research is warranted.

Dataset Information

11C-hydroxy-ephedrine-PET/CT in the Diagnosis of Pheochromocytoma and Paraganglioma.

Publications

<sup>11</sup>C-hydroxy-ephedrine-PET/CT in the Diagnosis of Pheochromocytoma and Paraganglioma.

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