Abstract
MPP (malignant paragangliomas and pheochromocytomas) are rare neuroendocrine tumors that can be associated with succinate dehydrogenase subunits (SDHx) germline mutations. SDH encodes for a TCA enzyme that catalyzes the oxidation of succinate to fumarate. When mutated SDH losses its function, leading to succinate accumulation. We have evaluated serum succinate levels as a new biomarker in SDHx-mutated MPP patients. Retrospective monocentric study of 88 MPP patients (43 sporadic: SDHxWT; 45 mutated SDHx, among which 35 where SDHB) and 17 tumor-free familial asymptomatic carriers (SDH-B: 13, SDH-C: 2, SDH-D: 2). Clinical and biological data were available in all. 18F-FDG-PET was available in 32 metastatic MPP (15 sporadic, 17 SDH-B). 18F-FDG-PET analyses were performed on an Advantage Workstation (GE Healthcare). A healthy control group (n=10) is included. Serum succinate levels (n=290) were quantified by LC-MS/MS (Waters). Statistical analyses were performed with GraphpadPrism®. Serum succinate levels were increased in the disease-free SDHx group (median: 7.3 μM) compared to the control group (median: 4.8 μM). Succinate levels >6.9 μM allowed to identify disease-free SDHx mutated cases compared to the healthy control group (100% specificity; 85% sensitivity). When tumor is detected, mutated SDH-B patients had a significantly increased median succinate level (13.5 μM) compared to sporadic patients (7.9 μM) (p<0.01). Metastatic SDH-B patients showed a higher median succinate level (14.9 μM). Extension of the metastatic disease evaluated by the total lesion glycolysis (TLG) activity (18F-FDG-PET) was correlated to the succinate levels (r=0.76). In the SDHB group, patients with the highest tumor burden (3rd and 4th TLG quartiles) showed significant increased succinate levels compared to the sporadic group (p<0.001). Serum succinate is a metabolic biomarker that might be useful to identify SDHx mutated carriers (tumor-free familial asymptomatic carriers and metastatic MPP patients) and as a marker of metabolic tumor burden in patients with metastatic MPP.
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