Precision imaging and evolving therapies in paragangliomas and pheochromocytomas: from molecular diagnostics to imaging-guided management

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors originating from neural crest-derived chromaffin tissue, marked by clinical heterogeneity and substantial genetic underpinnings. With up to 70% of cases linked to germline or somatic mutations, including Succinate DeHydrogenase genetic alterations (SDHx), and Von Hippel-Lindau (VHL), genetic profiling is central to diagnosis, risk stratification, and therapeutic planning. Clinical presentation varies by tumor location and secretory status-from catecholamine-driven crises to mass effect in head and neck paragangliomas (H&N PGLs). The diagnostic workflow begins with biochemical testing, followed by high-resolution anatomical and functional imaging. Computed tomography (CT) and magnetic resonance imaging (MRI) remain essential for localization and staging, while radiopharmaceuticals such as ⁶⁸Ga-DOTA⁰-Tyr³-octreotate (⁶⁸Ga-DOTATATE), ¹⁸F-fluoro-L-dihydroxyphenylalanine (¹⁸F-FDOPA), and ¹³¹I-metaiodobenzylguanidine (¹³¹I-MIBG) refine tumor characterization and guide peptide receptor radiopharmaceutical therapy (RPT) with radiolabeled octreotide derivatives or therapeutic MIBG Imaging features such as size, necrosis, and diffusion restriction correlate with malignancy risk, but novel molecular imaging offer promise for more precise prognostication. Therapeutic options span from curative surgery to systemic therapies, including temozolomide, tyrosine kinase inhibitors, and nuclide therapy. Minimally invasive, image-guided interventions provide palliation for metastatic or inoperable disease. Importantly, artificial intelligence and molecular assays such as the NETest and ¹H-MRS are emerging as pivotal tools in real-time tumor monitoring, early relapse detection, and biomarker discovery. This review underscores the necessity of a multidisciplinary, genomics-informed, and imaging-guided approach to PPGL management. With the integration of advanced imaging and AI-driven analytics, precision oncology for PPGLs is transitioning from potential to practice. CRITICAL RELEVANCE STATEMENT: This article offers an overview of the diverse manifestations of paragangliomas, illustrated with examples from various anatomical locations. It also highlights different patterns of tumor evolution and provides an up-to-date review of current management and therapeutic strategies, with a special focus on emerging AI-guided approaches. KEY POINTS: Review the genetic associations, including Von Hippel-Lindau, Multiple Endocrine Neoplasia, Neurofibromatosis, and Carney Triad. Overview of anatomical imaging features (CT and MRI) of paragangliomas. Improve knowledge about the different Nuclear Medicine and functional imaging techniques in detecting lesions, depending on their location, secretory function and underlying genetic mutation. Discuss the multiple radiopharmaceuticals available for Scintigraphy and PET-CT, according to the paraganglioma site and mutational pattern.