Genetic screening in the clinical management of pheochromocytomas and paragangliomas

Pheochromocytomas and paragangliomas (PPGLs) are rare neural crest-derived neuroendocrine tumors characterized by excessive catecholamine secretion. More than 20 germline and somatic driver genes have been identified in PPGLs, with functional alterations converging on three core molecular clusters: pseudohypoxia, kinase signaling, and Wnt signaling. These clusters essentially regulate PPGL initiation, progression, and metastatic potential. Based on genotypic features and molecular clustering, this review establishes an integrated genotype-guided clinical framework covering the full clinical spectrum of PPGL management. The framework includes genotype-related biochemical phenotyping, optimized anatomical and functional imaging strategies, individualized surgical plans, stratified selection of radionuclide and targeted therapy, and risk-adapted surveillance schedules. This review also clarifies the clinical value of key biomarkers such as SDHx, VHL, and RET mutations, TERT methylation, and MAML3 fusions, which improve metastatic risk stratification and enable genotype-tailored surgical and therapeutic strategies for PPGLs. Integrating genetic data into routine clinical practice promotes a key paradigm shift in PPGL management, shifting conventional empirical care to precise genotype-based management. This strategy supports individualized surveillance, targeted prophylactic intervention, and matched precision therapy, and ultimately improves long-term clinical outcomes for patients with PPGLs.