The relation between clinical course of pheochromocytoma-paraganglioma (PPGL) and complex genetic etiology

Abstract

Recent years brought a remarkable progress on understanding the pathophysiology of rare, neuroendocrine tumours– pheochormocytomas and paragangliomas (PPGLs). Approximately 70% PPGLs are associated with germline or somatic mutation in one of more than 25 identified susceptibility genes, which were grouped into three clusters.Cluster 1 includes genes encoding proteins involved in Krebs cycle and hypoxia pathway – cluster 1 related PPGL are usually located extra-adrenally (often manifest as head and neck paragangliomas), they are also characterized by noradrenergic/dopaminergic biochemical phenotype and increased metastatic risk. Cluster 2 encompasses genes involved in kinase signaling pathway, PPGL related to cluster 2 are predominantly pheochromocytomas with adrenergic biochemical phenotype, the patients rarely develop metastases. The least known cluster 3, associated with deregulation of Wnt signaling pathway, includes exclusively somatic mutations leading to aggressive pheochromocytomas.This review summarizes molecular background and the differences between PPGL clusters regarding clinical course, biochemical phenotype, optimal imaging modalities and targeted molecular therapies for metastatic PPGL.