Personalized Management of Pheochromocytoma and Paraganglioma

• Published in: Endocrine reviews 2022-04, Vol.43 (2), p.199-239
• Main Authors: Nölting, Svenja, Bechmann, Nicole, Taieb, David, Beuschlein, Felix, Fassnacht, Martin, Kroiss, Matthias, Eisenhofer, Graeme, Grossman, Ashley, Pacak, Karel
• Format: Article
• Language: English
• Subjects: Adrenal Gland Neoplasms - diagnosis; Adrenal Gland Neoplasms - genetics; Adrenal Gland Neoplasms - therapy; Customization; Development and progression; Disease susceptibility; Droperidol; Gene mutations; Germ-Line Mutation; Heritability; Humans; Kinases; Krebs cycle; Metastases; Metastasis; Molecular clusters; Mutation; Neuroendocrine tumors; Paraganglioma; Paraganglioma - diagnosis; Paraganglioma - genetics; Paraganglioma - therapy; Patients; Phenotypes; Pheochromocytoma; Pheochromocytoma - diagnosis; Pheochromocytoma - genetics; Pheochromocytoma - therapy; Review; Sibutramine; Signs and symptoms; Tricarboxylic acid cycle; Tumors; White people; Wnt protein
• ISSN: 0163-769X; 1945-7189
• DOI: 10.1210/endrev/bnab019

Abstract Pheochromocytomas/paragangliomas are characterized by a unique molecular landscape that allows their assignment to clusters based on underlying genetic alterations. With around 30% to 35% of Caucasian patients (a lower percentage in the Chinese population) showing germline mutations in susceptibility genes, pheochromocytomas/paragangliomas have the highest rate of heritability among all tumors. A further 35% to 40% of Caucasian patients (a higher percentage in the Chinese population) are affected by somatic driver mutations. Thus, around 70% of all patients with pheochromocytoma/paraganglioma can be assigned to 1 of 3 main molecular clusters with different phenotypes and clinical behavior. Krebs cycle/VHL/EPAS1-related cluster 1 tumors tend to a noradrenergic biochemical phenotype and require very close follow-up due to the risk of metastasis and recurrence. In contrast, kinase signaling–related cluster 2 tumors are characterized by an adrenergic phenotype and episodic symptoms, with generally a less aggressive course. The clinical correlates of patients with Wnt signaling–related cluster 3 tumors are currently poorly described, but aggressive behavior seems likely. In this review, we explore and explain why cluster-specific (personalized) management of pheochromocytoma/paraganglioma is essential to ascertain clinical behavior and prognosis, guide individual diagnostic procedures (biochemical interpretation, choice of the most sensitive imaging modalities), and provide personalized management and follow-up. Although cluster-specific therapy of inoperable/metastatic disease has not yet entered routine clinical practice, we suggest that informed personalized genetic-driven treatment should be implemented as a logical next step. This review amalgamates published guidelines and expert views within each cluster for a coherent individualized patient management plan. Graphical Abstract Graphical Abstract