Charlotte Lussey-Lepoutre1,2, Alexandre Bellucci3, Nelly Burnichon4,5, Laurence Amar4,6, Alexandre Buffet4,7, Tom Drossart4,5, Sébastien Fontaine3, Olivier Clement3,4, Paule Benit8, Pierre Rustin8, Lionel Groussin9,10, Tchao Meatchi11, Anne-Paule Gimenez-Roqueplo4,5, Bertrand Tavitian3,4, Judith Favier4. 1. Department of Nuclear Medicine, Sorbonne Université, AP-HP, Pitie-Salpêtrière Hospital, F-75013, Paris, France. charlotte.lussey@inserm.fr. 2. PARCC, INSERM, Equipe Labellisée par la Ligue contre le Cancer, F-75015, Paris, France. charlotte.lussey@inserm.fr. 3. Radiology department, AP-HP, Hôpital Européen Georges Pompidou, F-75015, Paris, France. 4. Université de Paris, PARCC, INSERM, Equipe Labellisée par la Ligue contre le Cancer, F-75015, Paris, France. 5. Genetic department, adrenal referral center, AP-HP, Hôpital Européen Georges Pompidou, F-75015, Paris, France. 6. Hypertension Unit, adrenal referral center and EURACAN, AP-HP, Hôpital Européen Georges Pompidou, F-75015, Paris, France. 7. Clinical Investigation Center, AP-HP, Hôpital Européen Georges Pompidou, F-75015, Paris, France. 8. Hôpital Robert Debré, Université de Paris, NeuroDiderot, Inserm UMR1141, F-75015, Paris, France. 9. INSERM UMR1016 et CNRS UMR 8104, Institut Cochin, Université de Paris, Paris, France. 10. Department of Endocrinology, APHP, Cochin Hospital, Paris, France. 11. Department of Pathology, AP-HP, Hôpital Européen Georges Pompidou, Paris, France.
Abstract
PURPOSE: Germline mutations in genes encoding succinate dehydrogenase (SDH) are frequent in patients with pheochromocytoma and paraganglioma (PPGL). They lead to SDH inactivation, mediating a massive accumulation of succinate, which constitutes a highly specific biomarker of SDHx-mutated tumors when measured in vitro. In a recent pilot study, we showed that magnetic resonance spectroscopy (1H-MRS) optimized for succinate detection (SUCCES) could detect succinate in vivo in both allografted mouse models and PPGL patients. The objective of this study was to prospectively assess the diagnostic performances of 1H-MRS SUCCES sequence for the identification of SDH deficiency in PPGL patients. METHODS: Forty-nine patients presenting with 50 PPGLs were prospectively enrolled in our referral center for 1H-MRS SUCCES. Two observers blinded to the clinical characteristics and genetic status analyzed the presence of a succinate peak and confronted the results to a composite gold standard combining PPGL genetic testing and/or in vitro protein analyses in the tumor. RESULTS: A succinate peak was observed in 20 tumors, all of which had proven SDH deficiency using the gold standard (17 patients with germline SDHx mutations, 2 with a somatic SDHD mutation, and 1 with negative SDHB IHC and SDH loss of function). A false negative result was observed in 3 tumors. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 1H-MRS SUCCES were respectively 87%, 100%, 100%, 90%, and 94%. CONCLUSIONS: Detection of succinate using 1H-MRS is a highly specific and sensitive hallmark of SDH-deficiency in PPGLs.
PURPOSE: Germline mutations in genes encoding succinate dehydrogenase (SDH) are frequent in patients with pheochromocytoma and paraganglioma (PPGL). They lead to SDH inactivation, mediating a massive accumulation of succinate, which constitutes a highly specific biomarker of SDHx-mutated tumors when measured in vitro. In a recent pilot study, we showed that magnetic resonance spectroscopy (1H-MRS) optimized for succinate detection (SUCCES) could detect succinate in vivo in both allografted mouse models and PPGL patients. The objective of this study was to prospectively assess the diagnostic performances of 1H-MRS SUCCES sequence for the identification of SDH deficiency in PPGL patients. METHODS: Forty-nine patients presenting with 50 PPGLs were prospectively enrolled in our referral center for 1H-MRS SUCCES. Two observers blinded to the clinical characteristics and genetic status analyzed the presence of a succinate peak and confronted the results to a composite gold standard combining PPGL genetic testing and/or in vitro protein analyses in the tumor. RESULTS: A succinate peak was observed in 20 tumors, all of which had proven SDH deficiency using the gold standard (17 patients with germline SDHx mutations, 2 with a somatic SDHD mutation, and 1 with negative SDHB IHC and SDH loss of function). A false negative result was observed in 3 tumors. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 1H-MRS SUCCES were respectively 87%, 100%, 100%, 90%, and 94%. CONCLUSIONS: Detection of succinate using 1H-MRS is a highly specific and sensitive hallmark of SDH-deficiency in PPGLs.
Entities:
Keywords:
Magnetic resonance spectroscopy; Paraganglioma; Succinate; Succinate dehydrogenase
Authors: Arthur Varoquaux; Yann le Fur; Alessio Imperiale; Antony Reyre; Marion Montava; Nicolas Fakhry; Izzie-Jacques Namer; Guy Moulin; Karel Pacak; Maxime Guye; David Taïeb Journal: Endocr Relat Cancer Date: 2015-06-26 Impact factor: 5.678
Authors: P J Pollard; J J Brière; N A Alam; J Barwell; E Barclay; N C Wortham; T Hunt; M Mitchell; S Olpin; S J Moat; I P Hargreaves; S J Heales; Y L Chung; J R Griffiths; A Dalgleish; J A McGrath; M J Gleeson; S V Hodgson; R Poulsom; P Rustin; I P M Tomlinson Journal: Hum Mol Genet Date: 2005-06-29 Impact factor: 6.150
Authors: Susan Richter; Mirko Peitzsch; Elena Rapizzi; Jacques W Lenders; Nan Qin; Aguirre A de Cubas; Francesca Schiavi; Jyotsna U Rao; Felix Beuschlein; Marcus Quinkler; Henri J Timmers; Giuseppe Opocher; Massimo Mannelli; Karel Pacak; Mercedes Robledo; Graeme Eisenhofer Journal: J Clin Endocrinol Metab Date: 2014-07-11 Impact factor: 5.958
Authors: Jyotsna U Rao; Udo F H Engelke; Richard J T Rodenburg; Ron A Wevers; Karel Pacak; Graeme Eisenhofer; Nan Qin; Benno Kusters; Angelina G Goudswaard; Jacques W M Lenders; Ad R M M Hermus; Arjen R Mensenkamp; Henricus P M Kunst; Fred C G J Sweep; Henri J L M Timmers Journal: Clin Cancer Res Date: 2013-05-30 Impact factor: 12.531
Authors: Ruth T Casey; Mary A McLean; Basetti Madhu; Benjamin G Challis; Rogier Ten Hoopen; Thomas Roberts; Graeme R Clark; Deborah Pittfield; Helen L Simpson; Venkata R Bulusu; Kieran Allinson; Lisa Happerfield; Soo-Mi Park; Alison Marker; Olivier Giger; Eamonn R Maher; Ferdia A Gallagher Journal: JCO Precis Oncol Date: 2018-03-29
Authors: Thomas G Papathomas; Diederik P D Suurd; Alfred K Lam; Ronald R de Krijger; Karel Pacak; Arthur S Tischler; Menno R Vriens Journal: Endocr Pathol Date: 2021-01-12 Impact factor: 3.943
Authors: Edward P Lin; Bennett B Chin; Lauren Fishbein; Toshio Moritani; Simone P Montoya; Shehanaz Ellika; Shawn Newlands Journal: Radiol Imaging Cancer Date: 2022-05