Rethinking paraganglioma management: distinct clinical pathways for head and neck versus other sites

Paragangliomas (PGLs) are rare neuroendocrine tumors that arise from the paraganglionic tissues and are associated with the autonomic nervous system. Although traditionally classified conjointly, head and neck PGLs (HNPGLs) and PGLs located outside the head and neck (PGLOs) exhibit distinct embryological origins, genetic predispositions, functional profiles, clinical behavior, and therapeutic strategies. HNPGLs are typically nonfunctional and arise from parasympathetic tissues, whereas PGLOs often originate from sympathetic tissues, are frequently functional, and secrete catecholamines. Recent advances in molecular genetics, particularly those involving SDHx mutations, have revealed genotype-phenotype correlations that further differentiate these tumor groups. Despite overlapping histopathological features, the natural history, risk of malignancy, and surveillance strategies differ substantially. Although surgical resection remains the mainstay of treatment for both HNPGLs and PGLOs, the indications, risks, and outcomes vary according to tumor location and genetic context. This review aims to provide a comprehensive clinical comparison between HNPGLs and PGLOs, outlining their unique anatomical, genetic, and clinical characteristics. We emphasize the importance of site-specific management strategies that consider both functional status and prognosis. Based on these distinctions, we propose a revised diagnostic and therapeutic framework that surpasses a uniform classification and emphasizes precision medicine for the management of PGLs. This approach could reduce treatment-related morbidity, optimize long-term outcomes, and guide genetic counseling and surveillance in affected individuals and their families.