SDHB mutation status and tumor size but not tumor grade are important predictors of clinical outcome in pheochromocytoma and abdominal paraganglioma

Assadipour, Yasmine; Sadowski, Samira M.; Alimchandani, Meghna; Quezado, Martha; Steinberg, Seth M.; Nilubol, Naris; Patel, Dhaval; Prodanov, Tamara; Pacák, Karel; Kebebew, Electron

doi:10.1016/j.surg.2016.05.050

Cited by 67 publications

(51 citation statements)

References 23 publications

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“…47 In the past, several studies have shown an association between SDHB-related metastatic PGL/PCC and a shorter survival in patients compared to sporadic metastatic PGL/PCC. 48,49 In a recent analysis of Hescot et al, not the SDHB mutation status but hypersecretion of metanephrines and chromogranin A was found to be a significant prognostic factor for worst overall survival. 50 Other SDHB-associated tumors include RCC, although the risk for this manifestation seems low, varying between 4.7% and 8%.…”

Section: Sdhb Mutationsmentioning

confidence: 98%

“…In a recent meta‐analysis of the outcomes of metastatic PGL and PCC, Hamidi et al found that the overall mortality in SDHB mutation carriers ranged from 35% to 55% (n = 96) compared to an overall mortality of 53% (95% confidence interval 43%‐63%) in the whole group of PGL/PCC . In the past, several studies have shown an association between SDHB ‐related metastatic PGL/PCC and a shorter survival in patients compared to sporadic metastatic PGL/PCC . In a recent analysis of Hescot et al, not the SDHB mutation status but hypersecretion of metanephrines and chromogranin A was found to be a significant prognostic factor for worst overall survival …”

Section: Phenotype Of Sdhx Mutation Carriersmentioning

confidence: 99%

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Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

et al. 2019

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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. K E Y W O R D S oncometabolites, paraganglioma, pheochromocytoma, SDH mutation, succinate 1 | INTRODUCTION Mutations of genes encoding for the succinate dehydrogenase (SDH) complex, associated with familial paraganglioma (PGL) and pheochromocytoma (PCC), lead to accumulation of succinate, which disturbs the metabolic regulation of the cell. Nowadays metabolic dysregulation is recognized as one of the eight hallmarks of cancer. 1 Although germline mutations in SDHx genes are predominantly linked to PGL and PCC, these mutations also predispose to renal cell carcinoma (RCC), gastrointestinal stromal tumors (GISTs) and, possibly, pituitary adenomas. PCC, PGL and head and neck PGL (HNPGL) are rare neuroendocrine tumors arising from chromaffin cells that can synthesize and release catecholamines. Sympathetic PGLs are derived from sympathetic paraganglia in the chest, abdomen or pelvis. PCC are PGLs located in the adrenal medulla. 2 HNPGLs are derived from parasympathetic paraganglia. Common locations for HNPGLs include the carotid body and the middle ear, as well as the vagus nerve and internal jugular vein. While parasympathetic PGLs are most often non-functional tumors, PCC and sympathetic PGL release catecholamines into the circulation and can

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Section: Sdhb Mutationsmentioning

confidence: 98%

Section: Phenotype Of Sdhx Mutation Carriersmentioning

confidence: 99%

Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

et al. 2019

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“…If left untreated, a subset of these tumors will metastasize. A high malignant potential has been specifically recognized for SDHB-related tumors and is associated with tumor size at the time of diagnosis (40,41). The increased metastatic potential and aggressive nature of SDHx-related paragangliomas compared with de novo paragangliomas without underlying germline predisposition must be taken into account when developing early tumor surveillance in patients with HPP.…”

Section: Introductionmentioning

confidence: 99%

Von Hippel–Lindau and Hereditary Pheochromocytoma/Paraganglioma Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood

Rednam

Erez

Druker

et al. 2017

Clinical Cancer Research

214

157

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Von Hippel-Lindau disease (vHL) is a hereditary tumor predisposition syndrome that places affected individuals at risk for multiple tumors, which are predominantly benign and generally occur in the central nervous system or abdomen. Although the majority of tumors occur in adults, children and adolescents with the condition develop a significant proportion of vHL manifestations and are vulnerable to delayed tumor detection and their sequelae. Although multiple tumor screening paradigms are currently being utilized for patients with vHL, surveillance should be reassessed as the available relevant clinical information continues to expand. We propose a new vHL screening paradigm similar to existing approaches, with important modifications for some tumor types, placing an emphasis on risks in childhood. This includes advancement in the timing of surveillance initiation and increased frequency of screening evaluations. Another neuroendocrine-related familial condition is the rapidly expanding hereditary paraganglioma and pheochromocytoma syndrome (HPP). The tumor spectrum for patients with HPP syndrome includes paragangliomas, pheochromocytomas, renal cancer, and gastrointestinal stromal tumors. The majority of patients with HPP syndrome harbor an underlying variant in one of the SHDx genes (SDHA, SDHB, SDHC, SDHD, SDHA, and SDHAF2), although other genes also have been described (MAX and TMEM127). Annual screening for elevated plasma or urine markers along with complete blood count and biennial whole-body MRI accompanied by focal neck MRI is recommended for older children and adults with HPP syndrome to detect tumors early and to decrease morbidity and mortality from HPP-related tumors.

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“…SDHB mutations, which cause paraganglioma syndrome type 4, are associated with the highest malignancy rates among chromaffin tumours, ranging from 29 to 73·8 per cent, and SDHB ‐related malignancy in turn portends a 5‐year survival rate of 36 per cent. However, although most patients develop hypersecreting thoracoabdominal paragangliomas, data on malignancy, mortality or treatment outcomes specifically for primary adrenal tumours have not been clearly delineated in studies, partly because of ambiguous use of the terms ‘paraganglioma’ and ‘phaeochromocytoma’, and probably also due to a relatively low prevalence (6·4–28 per cent) among these patients.…”

Section: Sdhx Mutations In Paraganglioma Syndromes Types 1–5mentioning

confidence: 99%

Extent of surgery for phaeochromocytomas in the genomic era

Rossitti

Söderkvist

Gimm

2018

British Journal of Surgery

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Adrenal-sparing surgery should be the standard approach for patients who have already been diagnosed with MEN2 or VHL when operating on the first side, whereas complete removal of the affected adrenal gland(s) is generally recommended for patients with SDHB or MAX germline mutations. Routine assessment of a patient's genotype, even after the first operation, can be crucial for adopting an appropriate strategy for follow-up and future surgery.

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SDHB mutation status and tumor size but not tumor grade are important predictors of clinical outcome in pheochromocytoma and abdominal paraganglioma

Cited by 67 publications

References 23 publications

Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

Von Hippel–Lindau and Hereditary Pheochromocytoma/Paraganglioma Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood

Extent of surgery for phaeochromocytomas in the genomic era

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