Biomarkers of metastatic disease in pheochromocytoma and paraganglioma

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors with variable metastatic potential. While metastatic disease occurs in approximately 10–20% of cases, its prediction remains a major clinical challenge, as no histological system has been universally validated to reliably identify aggressive tumors at diagnosis. This review aims to provide a comprehensive and updated overview of current and emerging biomarkers of metastatic risk in PPGL, encompassing histopathological scoring systems, genetic and molecular markers, biochemical phenotyping, liquid biopsy approaches, and imaging-based biomarkers. Among established markers, germline SDHB mutation status, loss of SDHB expression by immunohistochemistry, elevated plasma 3-methoxytyramine, and histopathological scoring systems such as GAPP and COPPS represent the most clinically validated tools for risk stratification. Emerging biomarkers — including somatic alterations in ATRX and TERT, genomic instability indices, tumor immune microenvironment characterization, circulating tumor DNA, and oncometabolite quantification — show promise in refining prognostic assessment but require prospective validation before routine clinical implementation. Accurate risk stratification in PPGL demands a multiparametric and dynamic approach, integrating clinical, genetic, biochemical, and molecular parameters. Future progress will depend on large prospective international cohorts, standardized biomarker platforms, and biomarker-driven clinical trial designs to translate emerging molecular knowledge into improved patient outcomes.