The Molecular Classification of Pheochromocytomas and Paragangliomas: Discovering the Genomic and Immune Landscape of Metastatic Disease

Abstract Pheochromocytomas (PCCs) and paragangliomas (PGLs, together PPGLs) are the most hereditary tumors known. PPGLs were considered benign, but the fourth edition of the World Health Organisation (WHO) classification redefined all PPGLs as malignant neoplasms with variable metastatic potential. The metastatic rate differs based on histopathology, genetic background, size, and location of the tumor. The challenge in predicting metastatic disease lies in the absence of a clear genotype–phenotype correlation among the more than 20 identified genetic driver variants. Recent advances in molecular clustering based on underlying genetic alterations have paved the way for improved cluster-specific personalized treatments. However, despite some clusters demonstrating a higher propensity for metastatic disease, cluster-specific therapies have not yet been widely adopted in clinical practice. Comprehensive genomic profiling and transcriptomic analyses of large PPGL cohorts have identified potential new biomarkers that may influence metastatic potential. It appears that no single biomarker alone can reliably predict metastatic risk; instead, a combination of these biomarkers may be necessary to develop an effective prediction model for metastatic disease. This review evaluates current guidelines and recent genomic and transcriptomic findings, with the aim of accurately identifying novel biomarkers that could contribute to a predictive model for mPPGLs, thereby enhancing patient care and outcomes.