Presurgical Succinate MetAstatic Risk Tool (P-SMART) in Paragangliomas

Paragangliomas (PGLs) are rare malignant non-epithelial neuroendocrine neoplasms characterized by a strong genetic determinism and heterogeneous metastatic potential with no reliable histopathological predictors. In this retrospective study we investigated the role of serum succinate as a biomarker for metastatic risk and developed a novel preoperative scoring tool.

Seventy patients with PGLs evaluated between 2006 and 2023 were analysed. Clinical, biochemical, imaging, and genetic data were collected. Germline genetic variants were analysed via Sanger sequencing or NGS through a targeted panel of susceptibility genes. Serum succinate concentrations were quantified by gas chromatography-mass spectrometry.

Succinate levels were significantly higher in patients with Cluster 1 genetic variants (p < 0.001), extra-adrenal PGLs (p = 0.006), and metastatic disease (p = 0.024). We developed a novel preoperative risk assessment tool, the P-SMART (Preoperative Succinate MetAstatic Risk Tool), combining serum succinate levels, tumour size, and location. P-SMART assigns: 3 points for extra-adrenal localization, 3.5 points for serum succinate ≥ 8.95 µM, and 3 points for tumour size ≥ 7.0 cm. In our cohort a P-SMART score > 4.75 predicted metastatic disease with 72.7% sensitivity and 83% specificity, outperforming the ASES score (Age, Size, Extra-adrenal, Secretory type; AUC 0.891 vs 0.752, p = 0.005).

Though limited by sample size and retrospective design, our findings suggest that succinate is a minimally invasive biomarker that could enhance preoperative metastatic risk stratification, especially when integrated into a multiparametric score such as P-SMART. Larger prospective studies are needed to validate its role, but P-SMART could optimize clinical decision-making, refine patient selection for whole-body imaging, reduce unnecessary radiation exposure, and inform surveillance strategies.