Pheochromocytoma and Extra-Adrenal Paragangliomas: An Update in Diagnostics and Clinical Implications

Over the last 2 to 3 decades, we have seen incremental movement from the “Rule of 10s” for pheochromocytomas, particularly those regarding tumor bilaterality, malignancy, and patterns of inheritance. The biology and prevalence of these tumors have not changed, but there has been a great deal of progress in terms of our understanding of tumor genetics, variable modes of acquiring of both pheochromocytomas and paragangliomas (PPGL), and our approach to clinical management of these unpredictable neoplasias. Although these non-epithelial neuroendocrine tumors are rare, they are clinically significant due to their hormonal activity, association with hereditary syndromes, and biological potential. Their detection has increased in recent decades with improved biochemical testing and advanced imaging modalities, yet predicting clinical behavior continues to be a major challenge. Histologically, PPGL typically shows classic neuroendocrine architecture but may display morphologic diversity, occasionally mimicking other adrenal or paraganglionic tumors. Immunohistochemistry remains essential for diagnostic confirmation and as a surrogate for genetic alterations, offering valuable genotype-phenotype correlations. With increasing knowledge of tumor genetics, additional emphasis has been placed on histology-based risk-stratification for these lesions, particularly those prone to metastasis or multifocality, and the 2022 WHO endorses no individual risk-stratification system, as none seems to be of definitive merit over another. Instead, it promotes a comprehensive approach integrating morphologic, molecular, and clinical factors. Approximately 40% of PPGL harbor germline mutations, whereas somatic alterations account for additional subsets. Mutations in SDH x, VHL , RET , NF1 , and other susceptibility genes define molecular clusters with distinct signaling pathways and clinical behavior, underscoring the importance of multidisciplinary, lifelong management.