Journal of Genomics and Precision Medicine

ABSTRACT

Pheochromocytoma and paraganglioma (PPGL) constitute a uniquely complex group of neuroendocrine tumors in which rare incidence contrasts sharply with disproportionate clinical impact. Despite their low prevalence, PPGLs pose a persistent diagnostic and therapeutic challenge due to their high genetic heterogeneity, unpredictable clinical behavior, and potential for life-threatening catecholamine-mediated complications. Over the past decade, advances in genomic profiling have overturned the traditional view of PPGL as largely sporadic and benign, revealing that up to 40% of cases are driven by germline pathogenic variants, with additional somatic alterations shaping tumor aggressiveness and metastatic risk.

Nevertheless, major unresolved gaps remain, including incomplete genotype–phenotype correlations, variable penetrance even within the same mutation, and the absence of universally accepted algorithms for integrating genetic data into routine clinical decision-making. These uncertainties directly affect risk stratification, surveillance intensity, and selection of emerging targeted and radionuclide therapies.

This review critically examines current evidence on the molecular architecture, biochemical phenotypes, and genotype-guided management of PPGLs, highlighting areas of consensus as well as ongoing controversies. By synthesizing recent translational and clinical insights, we aim to clarify why a genetics-centered, precision-based framework is no longer optional but essential for improving outcomes in PPGL.

Keywords: Pheochromocytoma; Paraganglioma; Genetic Susceptibility; Precision Medicine; Targeted Therapy