Personalized Management of Pheochromocytoma and Paraganglioma.

Svenja Nölting, Nicole Bechmann, David Taieb, Felix Beuschlein, Martin Fassnacht, Matthias Kroiss, Graeme Eisenhofer, Ashley Grossman, Karel Pacak

Journal: Endocrine reviews 2022;43(2):199-239

PMID: 34147030

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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.

Address: Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH), CH-8091 Zurich, Switzerland.; Department of Medicine IV, University Hospital, LMU Munich, 80336 Munich, Germany.; Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.; Department of Medicine III, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.; Department of Nuclear Medicine, La Timone University Hospital, CERIMED, Aix-Marseille University, 13273 Marseille, France.; Department of Medicine, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, 97080 Würzburg, Germany.; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX2 6HG, UK.; Centre for Endocrinology, Barts and the London School of Medicine, London EC1M 6BQ, UK.; ENETS Centre of Excellence, Royal Free Hospital, London NW3 2QG, UK.; Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Rockville, MD 20847, USA.

DOI: 10.1210/endrev/bnab019

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MeSH Terms: Adrenal Gland Neoplasms, Germ-Line Mutation, Humans, Mutation, Paraganglioma, Pheochromocytoma