Prognosis of Malignant Pheochromocytoma and Paraganglioma (MAPP-Prono Study): A European Network for the Study of Adrenal Tumors Retrospective Study

Hescot, Ségolène; Currás-Freixes, María; Deutschbein, Timo; Berkel, Anouk van; Vezzosi, Delphine; Amar, Laurence; Fouchardière, Christelle De La; Valdés, Nuria; Riccardi, Ferdinando; Cao, Christine Do; Bertherat, Jérôme; Goichot, B.; Beuschlein, Felix; Drui, Delphine; Canu, Letizia; Niccoli, Patricia; Laboureau, S.; Tabarin, Antoine; Leboulleux, Sophie; Calsina, Bruna; Libé, Rossella; Faggiano, Antongiulio; Schlumberger, Martin; Borson‐Chazot, Françoise; Mannelli, Massimo; Gimenez-Roqueplo, Anne-Paule; Caron, Philippe; Timmers, Henri J L M; Fassnacht, Martin; Robledo, Mercedes; Borget, Isabelle; Baudin, Éric

doi:10.1210/jc.2018-01968

Cited by 137 publications

(141 citation statements)

References 24 publications

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“…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: 98%

“…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%. 21,40 GISTs are reported to occur in approximately 2% of SDHB carriers.…”

Section: Sdhb Mutationsmentioning

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: Phenotype Of Sdhx Mutation Carriersmentioning

confidence: 98%

Section: Sdhb Mutationsmentioning

confidence: 99%

Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

et al. 2019

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“…In our study, for patients with ACC and PPGL, the non-metastatic had better OS and CSS. Poor survival was associated with synchronous metastasis, which can be seen in patients with PPGL [19][20][21][22] . Whereas for patients with SA, the non-metastatic group had a better OS, but there was no signi cant difference in CSS between the two groups.…”

Section: Discussionmentioning

confidence: 99%

Summary of clinical characteristics of common primary adrenal malignancies in adults

zhang¹,

wang²,

Li³

et al. 2020

Preprint

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Background To summary the clinical characteristics of common primary adrenal malignancies in adults, the survival time of the patients, and the prognostic factors associated with these rare malignancies. Methods The Surveillance, Epidemiology, and End Results database (1975–2016) was queried for all patients who were diagnosed with primary adrenal malignancies, including adrenocortical carcinoma(ACC), pheochromocytoma and paraganglioma (PPGL), lymphoma, and sarcoma (SA). The clinical characteristics, overall survival (OS) and cancer-specific survival (CSS) were analyzed, in which propensity score methodology, logistic regression modeling and Kaplan-Meier survival curves were used. The Multivariate Cox proportional hazard model was used to identify factors affecting the prognosis of patients with ACC. Results 3204 patients with primary adrenal malignancies were identified, including 2180 with ACC, 593 with PPGL, 307 with lymphoma, and 124 with SA. Generally, PPGL had a better prognosis than others. For ACC and PPGL, the non-metastatic group had better OS and CSS than the metastatic group; for SA, the non-metastatic group had better OS, however, there was no significant difference in CSS between the two groups. Furthermore, For ACC, the single metastasis group had a better OS than the multiple metastasis group. After tumors metastasis, the surgery group, surgery of primary adrenal lesions, had better OS and CSS than the non-surgery group for ACC and PPGL. For lymphoma, the chemotherapy group had better OS and CSS; for ACC and PPGL, the chemotherapy group had better CSS and worse OS; for SA, the survival showed no significant difference between the two groups. Radiotherapy had the same effect on patients' survival as chemotherapy, except for the lymphoma and the ACC. As for lymphoma, the radiotherapy group had better CSS, whereas the survival showed no significant difference in OS between the two groups. For ACC, the non- radiotherapy group had better CSS and OS. More importantly, for lymphoma, under the condition that both cohorts were the same basically, the surgical group had a better prognosis. The prognosis of ACC was related to sex, age, seer historic stage, surgery, chemotherapy. Conclusion Understanding the clinical characteristics of these tumors and factors affecting prognosis can facilitate the selection of more appropriate clinical treatment options.

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“…On subgroup analysis, SDHC-related PGLs were found to have higher 18 F-FDOPA uptake parameters, more particulary TL uptake compared to sporadic and SDHD ones. 7 It has also been shown that SDHB-related PPGL which are mostly of sympathetic origin are characterized by a greater propensity towards metastasis compared to other SDHx subgroups, 21,22 suggesting that beyond SDH deficiency common to SDHA/B/C/D mutants, additional events may promote an aggressive behaviour. The inter-and intra-patient differences observed on 18 F-FDOPA PET/CT in SDHx mutation carriers is still unexplainable.…”

Section: Discussionmentioning

confidence: 99%

“…It has also been shown that SDHB-related PPGL which are mostly of sympathetic origin are characterized by a greater propensity towards metastasis compared to other SDHx subgroups, 21,22 suggesting that beyond SDH deficiency common to SDHA/B/C/D mutants, additional events may promote an aggressive behaviour. The analysis of our three cases of metastatic HNPGL suggests that loss of 18 F-FDOPA uptake (immature phenotype) is not a prerequisite for metastatic spread and may occur at distant sites in host tissues.…”

Section: Discussionmentioning

confidence: 99%

Exploring the link between tumour metabolism and succinate dehydrogenase deficiency: A ¹⁸F‐FDOPA PET/CT study in head and neck paragangliomas

Reichert

Fakhry

Lavieille

et al. 2019

Clinical Endocrinology

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Objectives: Nuclear imaging findings by virtue of phenotyping disease heavily depend on genetic background, metabolites, cell membrane specific targets and signalling pathways. PPGL related to succinate dehydrogenase subunits mutations (SDHx mutations) are less differentiated than other subgroups and therefore may lack to concentrate 18 F-FDOPA, a precursor of catecholamines biosynthesis. However, this 18 F-FDOPA negative phenotype has been reported mostly in SDHx-PPGL of sympathetic origin, suggesting that both genotype status and location (from sympathetic vs parasympathetic paraganglia; adrenal vs extra-adrenal) could influence 18 F-FDOPA uptake. The aim of this study was to test if SDHx drives 18 F-FDOPA uptake in presence of normal epinephrine/norepinephrine concentrations. Design: Retrospective studyPatients: A cohort of 86 head and neck PPGL patients (including three metastatic) with normal metanephrines underwent 18 F-FDOPA PET/CT. The relationships between 18 F-FDOPA uptake and tumour genotype were evaluated. Results:In nonmetastatic HNPGL (50 non-SDHx/33 SDHx), no significant difference was observed between these two groups for SUVmax (P = .256), SUVmean (P = .188), MTV 42% (P = .596) and total lesion uptake (P = .144). Metastatic HNPGL also had high elevated uptake values. Conclusions:Our results suggest that SDH deficiency or metastatic behaviour have no influence on 18 F-FDOPA uptake in HNPGL probably due to their very-well differentiation status, even at metastatic stage. The potential prognosticator value of 18 F-FDOPA uptake would need to be further explored in the setting of metastatic PPGL of sympathetic origin.

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Prognosis of Malignant Pheochromocytoma and Paraganglioma (MAPP-Prono Study): A European Network for the Study of Adrenal Tumors Retrospective Study

Cited by 137 publications

References 24 publications

Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

Summary of clinical characteristics of common primary adrenal malignancies in adults

Exploring the link between tumour metabolism and succinate dehydrogenase deficiency: A ¹⁸F‐FDOPA PET/CT study in head and neck paragangliomas

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Prognosis of Malignant Pheochromocytoma and Paraganglioma (MAPP-Prono Study): A European Network for the Study of Adrenal Tumors Retrospective Study

Cited by 137 publications

References 24 publications

Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

Summary of clinical characteristics of common primary adrenal malignancies in adults

Exploring the link between tumour metabolism and succinate dehydrogenase deficiency: A 18F‐FDOPA PET/CT study in head and neck paragangliomas

Contact Info

Product

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Exploring the link between tumour metabolism and succinate dehydrogenase deficiency: A ¹⁸F‐FDOPA PET/CT study in head and neck paragangliomas