Paragangliomas and Pheochromocytomas: Integrating Developmental Biology With Translational Technologies. A Narrative...

Pheochromocytomas and paragangliomas (PGLs) are rare neural crest-derived neuroendocrine neoplasms with highly variable clinical behavior and limited therapeutic options in metastatic disease. From a pathology perspective, diagnosis and risk assessment have traditionally relied on histomorphology and immunohistochemistry. However, conventional parameters remain insufficient to reliably predict biological behavior. Over the past decade, genomic and transcriptomic profiling have refined molecular classification, yet genotype-based stratification alone does not fully explain heterogeneity in tumor progression, immune composition, or treatment response. This review examines the evolution of experimental and analytical approaches to PGLs through a pathology-centered lens. We first discuss how advances in developmental biology and molecular classification have reshaped understanding of tumor heterogeneity beyond morphology. We then highlight the growing recognition of the tumor microenvironment as a critical determinant of tumor behavior. In this context, spatially resolved protein profiling, including multiplex immunofluorescence (mIF), has emerged as an important extension of traditional immunohistochemistry, enabling simultaneous visualization of immune and tumor cell populations within preserved tissue architecture. These approaches provide functional insight that cannot be derived from bulk genomic analyses alone. Despite these advances, translation into therapeutic innovations has been hampered by the lack of physiologically relevant human model systems. Early two-dimensional cell cultures and rodent models provided foundational mechanistic insights but fail to recapitulate human tumor architecture and microenvironmental interactions. The recent establishment of patient-derived PGL organoids represents a significant step forward, preserving chromaffin lineage features and enabling ex vivo pharmacologic interrogation. Taken together, the progression from histopathological assessment to spatial immune profiling and advanced three-dimensional human modeling defines a conceptual framework in which functional therapeutic testing may become integrated into future pathology-driven translational research in PGLs.