Clinical implications of the oncometabolite succinate in SDHx-mutation carriers

Succinate dehydrogenase (SDH) mutations lead to the accumulation of succinate, which acts as an oncometabolite. Germline SDHx mutations predispose to paraganglioma (PGL) and pheochromocytoma (PCC), as well as to renal cell carcinoma and gastro-intestinal stromal tumors. The SDHx genes were the first tumor suppressor genes discovered which encode for a mitochondrial enzyme, thereby supporting Otto Warburg's hypothesis in 1926 that a direct link existed between mitochondrial dysfunction and cancer. Accumulation of succinate is the hallmark of tumorigenesis in PGL and PCC. Succinate accumulation inhibits several α-ketoglutarate dioxygenases, thereby inducing the pseudohypoxia pathway and causing epigenetic changes. Moreover, SDH loss as a consequence of SDHx mutations can lead to reprogramming of cell metabolism. Metabolomics can be used as a diagnostic tool, as succinate and other metabolites can be measured in tumor tissue, plasma and urine with different techniques. Furthermore, these pathophysiological characteristics provide insight into therapeutic targets for metastatic disease. This review provides an overview of the pathophysiology and clinical implications of oncometabolite succinate in SDHx mutations

Unilateral and Bilateral Adrenalectomy for Pheochromocytoma Requires Adjustment of Urinary and Plasma Metanephrine Reference Ranges

Context: Follow-up after adrenalectomy for pheochromocytoma is recommended because of a recurrence risk. During follow-up, plasma and/or urinary metanephrine (MN) and normetanephrine (NMN) are interpreted using reference ranges obtained in healthy subjects. Objective: Because adrenalectomy may decrease epinephrine production, we compared MN and NMN concentrations in patients after adrenalectomy to concentrations in a healthy reference population. Design: A single-center cohort study was performed in pheochromocytoma patients after adrenalectomy between 1980 and 2011. Subjects: Seventy patients after unilateral and 24 after bilateral adrenalectomy were included. Main Outcome Measures: Plasma-free and urinary-deconjugated MN and NMN determined at 3 to 6 months and annually until 5 years after adrenalectomy were compared with concentrations in a reference population. Data are presented in median (interquartile range). Results: Urinary and plasma MN concentrations 3 to 6 months after unilateral adrenalectomy were lower compared with the reference population (39 [31-53] mu mol/mol creatinine and 0.14 [0.09-0.18] nmol/L vs 61 [49-74] mu mol/mol creatinine and 0.18 [0.13-0.23] nmol/L, respectively, both P <.05). Urinary MN after bilateral adrenalectomy was reduced even further (7 [1-22] mu mol/mol creatinine; P <.05). Urinary and plasma NMN were higher after unilateral adrenalectomy (151 [117-189] mu mol/mol creatinine and 0.78 [0.59-1.00] nmol/L vs 114 [98-176] mu mol/mol creatinine and 0.53 [0.41-0.70] nmol/L; both P <.05). Urinary NMN after bilateral adrenalectomy was higher (177 [106-238] mu mol/mol creatinine; P <.05). Changes in urinary and plasma MNs persisted during follow-up. Conclusion: Concentrations of MN are decreased, whereas NMN concentrations are increased after unilateral and bilateral adrenalectomy. Adjusted reference values for MN and NMN are needed in the postsurgical follow-up of pheochromocytoma patients. (J Clin Endocrinol Metab 98:1076-1083, 2013

Calculating the optimal surveillance for head and neck paraganglioma in SDHB-mutation carriers

Germline mutations of the gene encoding succinate dehydrogenase subunit B (SDHB) predispose to head-and-neck-paraganglioma (HNPGL), sympathetic PGL, pheochromocytoma and renal cell carcinoma for which regular surveillance is required. SDHB-associated tumors harbor germline and somatic mutations, consistent with Knudson's two-hit hypothesis. To assess the penetrance and optimal surveillance for different manifestations of SDHB mutation carriers. This study included all SDHB mutation carriers who were followed at the Department of Endocrinology at the University Medical Center of Groningen. Kaplan-Meier curves were used to assess the penetrance. Poisson process was used to assess the optimal age to start surveillance and intervals. Ninety-one SDHB-mutation carriers (38 men and 53 women) were included. Twenty-seven mutation carriers (30 %) had manifestations, with an overall penetrance 35 % at the age of 60 years. We calculated that optimal surveillance for HNPGL could start from an age of 27 years with an interval of 3.2 years. This study underscores the relatively low penetrance of disease in SDHB mutation carriers. Use of the Poisson approach provides a more accurate estimation of the age to initiate surveillance and length of intervals for HNPGL. These results may give rise to reconsider the current guidelines regarding the screening of these mutation carriers

Efficacy of α-Blockers on Hemodynamic Control during Pheochromocytoma Resection: A Randomized Controlled Trial

CONTEXT: Pretreatment with α-adrenergic receptor blockers is recommended to prevent hemodynamic instability during resection of a pheochromocytoma or sympathetic paraganglioma (PPGL). OBJECTIVE: To determine which type of α-adrenergic receptor blocker provides the best efficacy. DESIGN: Randomized controlled open-label trial (PRESCRIPT; ClinicalTrials.gov NCT01379898). SETTING: Multicenter study including 9 centers in The Netherlands. PATIENTS: 134 patients with nonmetastatic PPGL. INTERVENTION: Phenoxybenzamine or doxazosin starting 2 to 3 weeks before surgery using a blood pressure targeted titration schedule. Intraoperative hemodynamic management was standardized. MAIN OUTCOME MEASURES: Primary efficacy endpoint was the cumulative intraoperative time outside the blood pressure target range (ie, SBP >160 mmHg or MAP <60 mmHg) expressed as a percentage of total surgical procedure time. Secondary efficacy endpoint was the value on a hemodynamic instability score. RESULTS: Median cumulative time outside blood pressure targets was 11.1% (interquartile range [IQR]: 4.3-20.6] in the phenoxybenzamine group compared to 12.2% (5.3-20.2)] in the doxazosin group (P = .75, r = 0.03). The hemodynamic instability score was 38.0 (28.8-58.0) and 50.0 (35.3-63.8) in the phenoxybenzamine and doxazosin group, respectively (P = .02, r = 0.20). The 30-day cardiovascular complication rate was 8.8% and 6.9% in the phenoxybenzamine and doxazosin group, respectively (P = .68). There was no mortality after 30 days. CONCLUSIONS: The duration of blood pressure outside the target range during resection of a PPGL was not different after preoperative treatment with either phenoxybenzamine or doxazosin. Phenoxybenzamine was more effective in preventing intraoperative hemodynamic instability, but it could not be established whether this was associated with a better clinical outcome

Efficacy of alpha-Blockers on Hemodynamic Control during Pheochromocytoma Resection:A Randomized Controlled Trial

CONTEXT: Pretreatment with α-adrenergic receptor blockers is recommended to prevent hemodynamic instability during resection of a pheochromocytoma or sympathetic paraganglioma (PPGL). OBJECTIVE: To determine which type of α-adrenergic receptor blocker provides the best efficacy. DESIGN: Randomized controlled open-label trial (PRESCRIPT; ClinicalTrials.gov NCT01379898). SETTING: Multicenter study including 9 centers in The Netherlands. PATIENTS: 134 patients with non-metastatic PPGL. INTERVENTION: phenoxybenzamine or doxazosin starting 2-3 weeks before surgery using a blood pressure targeted titration schedule. Intraoperative hemodynamic management was standardized. MAIN OUTCOME MEASURES: Primary efficacy endpoint was the cumulative intraoperative time outside the blood pressure target range (i.e., SBP >160 mmHg or MAP <60 mmHg) expressed as a percentage of total surgical procedure time. Secondary efficacy endpoint was the value on a hemodynamic instability score. RESULTS: Median cumulative time outside blood pressure targets was 11.1% [IQR: 4.3-20.6] in the phenoxybenzamine group compared to 12.2% [5.3-20.2] in the doxazosin group (P=0.75, r=0.03). The hemodynamic instability score was 38.0 [28.8-58.0] and 50.0 [35.3-63.8] in the phenoxybenzamine and doxazosin group, respectively (P=0.02, r=0.20). The 30-day cardiovascular complication rate was 8.8% and 6.9% in the phenoxybenzamine and doxazosin group, respectively (P=0.68). There was no mortality after 30 days. CONCLUSIONS: The duration of blood pressure outside the target range during resection of a PPGL was not different after preoperative treatment with either phenoxybenzamine or doxazosin. Phenoxybenzamine was more effective in preventing intraoperative hemodynamic instability, but it could not be established whether this was associated with a better clinical outcome

Emerging role of dopamine in neovascularization of pheochromocytoma and paraganglioma

Dopamine is a catecholamine that acts both as a neurotransmitter and as a hormone, exerting its functions via dopamine (DA) receptors that are present in a broad variety of organs and cells throughout the body. In the circulation, DA is primarily stored in and transported by blood platelets. Recently, the important contribution of DA in the regulation of angiogenesis has been recognized. In vitro and in vivo studies have shown that DA inhibits angiogenesis through activation of the DA receptor type 2. Overproduction of catecholamines is the biochemical hallmark of pheochromocytoma (PCC) and paraganglioma (PGL). The increased production of DA has been shown to be an independent predictor of malignancy in these tumors. The precise relationship underlying the association between DA production and PCC and PGL behavior needs further clarification. Herein, we review the biochemical and physiologic aspects of DA with a focus on its relations with VEGF and hypoxia inducible factor related angiogenesis pathways, with special emphasis on DA producing PCC and PGL.-Osinga, T. E., Links, T. P., Dullaart, R. P. F., Pacak, K., van der Horst-Schrivers, A. N. A., Kerstens, M. N., Kema, I. P. Emerging role of dopamine in neovascularization of pheochromocytoma and paraganglioma

Dopamine Excess in Patients with Head and Neck Paragangliomas

Aim: This study aimed to determine the prevalence of excess dopamine in relation to clinical symptoms and nuclear imaging in head and neck paraganglioma (PGL) patients. Patients and Methods: Thirty-six consecutive patients with head and neck PGLs, evaluated between 1993 and 2009, were included. Clinical symptoms, dopamine excess (urinary 3-methoxytyramine (3-MT) or dopamine and/or plasma dopamine or 3-MT) and (nor)epinephrine excess (urinary (nor)metanephrine) as well as (111)Inoctreotide and I-123-metaiodobenzylguanide (MIBG) scintigraphy were documented. Results: Dopamine excess was found in seven patients (19.4%), but was unrelated to clinical signs and symptoms. Excretion of other catecholamines was unremarkable, except in one patient with adrenal pheochrotnocytotna. I-123-MIBG uptake (present in 36.1% of patients) was associated with dopamine excess (p=0.03). Conclusion: Dopamine excess is present in a considerable percentage of patients with head and neck PGL, and its measurement may be useful in follow-up. Measurement of other catecholamines is necessary to rule out co-existent pheochromocytoma

Dopamine Excess in Patients with Head and Neck Paragangliomas

Aim: This study aimed to determine the prevalence of excess dopamine in relation to clinical symptoms and nuclear imaging in head and neck paraganglioma (PGL) patients. Patients and Methods: Thirty-six consecutive patients with head and neck PGLs, evaluated between 1993 and 2009, were included. Clinical symptoms, dopamine excess (urinary 3-methoxytyramine (3-MT) or dopamine and/or plasma dopamine or 3-MT) and (nor)epinephrine excess (urinary (nor)metanephrine) as well as (111)Inoctreotide and I-123-metaiodobenzylguanide (MIBG) scintigraphy were documented. Results: Dopamine excess was found in seven patients (19.4%), but was unrelated to clinical signs and symptoms. Excretion of other catecholamines was unremarkable, except in one patient with adrenal pheochrotnocytotna. I-123-MIBG uptake (present in 36.1% of patients) was associated with dopamine excess (p=0.03). Conclusion: Dopamine excess is present in a considerable percentage of patients with head and neck PGL, and its measurement may be useful in follow-up. Measurement of other catecholamines is necessary to rule out co-existent pheochromocytoma