Management of pheochromocytomas and paragangliomas: Review of current diagnosis and treatment options

Abstract

Pheochromocytomas (PCCs) are rare neuroendocrine tumors derived from the chromaffin cells of the adrenal medulla. When these tumors have an extra-adrenal location, they are called paragangliomas (PGLs) and arise from sympathetic and parasympathetic ganglia, particularly of the para-aortic location. Up to 25% of PCCs/PGLs are associated with inherited genetic disorders. The majority of PCCs/PGLs exhibit indolent behavior. However, according to their affiliation to molecular clusters based on underlying genetic aberrations, their tumorigenesis, location, clinical symptomatology, and potential to metastasize are heterogenous. Thus, PCCs/PGLs are often associated with diagnostic difficulties. In recent years, extensive research revealed a broad genetic background and multiple signaling pathways leading to tumor development. Along with this, the diagnostic and therapeutic options were also expanded. In this review, we focus on the current knowledge and recent advancements in the diagnosis and treatment of PCCs/PGLs with respect to the underlying gene alterations while also discussing future perspectives in this field.

Keywords: biomarkers; chemotherapy; molecular biology; prognostic factor; surgery; target therapy.

FIGURE 1

Treatment options in resectable, advanced, and metastatic PCCs/PGLs. PCC, pheochromocytoma; PGL, paraganglioma.

FIGURE 2

Therapeutic options: TKIs target multiple receptors and inhibit various signaling pathways. Radionuclides enter tumor cells through the specific NET1 receptor. Chemotherapy and PARP inhibitors block cell proliferation and growth at the level of DNA. Immunotherapy activates killer T cells by blocking the binding of PD‐1 and CTLA‐4 receptors with PD‐L1 and B7. HIF‐2α inhibitors block the interaction with a specific‐hypoxia responsive element (HRE) in the proximal region of the tyrosine‐hydroxylase promoter. Inhibition of the Wnt/β‐catenin pathway is promising therapy under investigation. Alterations in mitochondrial metabolism may lead to tumorigenesis. HIF, hypoxia‐inducible factor; TKI, tyrosine‐kinase inhibitor.