New Biology of Pheochromocytoma and Paraganglioma

Abstract

Pheochromocytomas and paragangliomas continue to be defined by significant morbidity and mortality despite their several recent advances in diagnosis, localization, and management. These adverse outcomes are largely related to mass effect as well as catecholamine-induced hypertension, tachyarrhythmias and consequent target organ damage, acute coronary syndromes, and strokes (ischemic and hemorrhagic stroke). Thus, a proper understanding of the physiology and pathophysiology of these tumors and recent advances are essential to affording optimal care. These major developments largely include a redefinition of metastatic behavior, a novel clinical categorization of these tumors into 3 genetic clusters, and an enhanced understanding of catecholamine metabolism and consequent specific biochemical phenotypes. Current advances in imaging of these tumors are shifting the paradigm from poorly specific anatomical modalities to more precise characterization of these tumors using the advent and development of functional imaging modalities. Furthermore, recent advances have revealed new molecular events in these tumors that are linked to their genetic landscape and, therefore, provide new therapeutic platforms. A few of these prospective therapies translated into new clinical trials, especially for patients with metastatic or inoperable tumors. Finally, outcomes are ever-improving as patients are cared for at centers with cumulative experience and well-established multidisciplinary tumor boards. In parallel, these centers have supported national and international collaborative efforts and worldwide clinical trials. These concerted efforts have led to improved guidelines collaboratively developed by healthcare professionals with a growing expertise in these tumors and consequently improving detection, prevention, and identification of genetic susceptibility genes in these patients.

Keywords: genetics; imaging; metanephrine; paraganglioma; pheochromocytoma; therapy.

Figure 1:

Most common symptoms and signs related to catecholamine excess found in patients with catecholamine-producing pheochromocytoma and paraganglioma. Diamond denotes symptoms and signs that are statistically different in patients with pheochromocytoma or paraganglioma compared to those without these tumors. Adapted from Lenders et al. (1).

Figure 2:

The action of various drugs affecting catecholamine synthesis, release, and reuptake. Metyrosine inhibits tyrosine hydroxylase and, therefore, catecholamine synthesis; sympathomimetics increase release of catecholamine from their storage vesicles; steroids may increase synthesis of catecholamines including their action on phenylethanolamine N-methyltransferase (converting norepinephrine to epinephrine); antidepressants block reuptake of catecholamines into pheochromocytoma cells and nerve terminals. Abbreviations: TH: tyrosine hydroxylase, DOPA: dihydroxyphenylalanine, PNMT: phenylethanolamine N-methyltransferase.

Figure 3:

Relationships of pre-test probability of pheochromocytoma or paraganglioma versus post-test probability of the presence of these tumors using the measurement of plasma free catecholamine metabolites. Adapted from Eisenhofer et al. (27).

Figure 4:

Pathophysiological, genetic, biochemical, and clinical characteristics of cluster 1 and 2 pheochromocytomas and paragangliomas. Abbreviations: DOPA: dihydroxyphenylalanine, PNMT: phenylethanolamine N-methyltransferase, NE: norepinephrine, EPI: epinephrine, VMAT: vesicular monoamine transporter, VHL: von Hippel-Lindau, SDH: succinate dehydrogenase, FH: fumarate hydratase, HIF2A: hypoxia-inducible factor 2α, RET: rearranged during transfection, NF1: neurofibromatosis type 1, TMEM127: transmembrane protein 127.

Figure 5:

The maximum intensity projection (MIP) images of the positron emission tomography/computed tomography (PET/CT) using radiopharmaceutical of choice across various genotypes is shown in this figure (coronal views). Top panel shows metastatic disease whereas the bottom panel shows primary tumors. Arrows in the figure represent the primary tumors. Abbreviations: SDHA/B/C/D: succinate dehydrogenase subunits A, B, C, D, VHL: von Hippel-Lindau, HNPGL: head and neck paraganglioma, HIF2A: hypoxia-inducible factor 2α, RET: rearranged during transfection, PHD1: prolyl hydroxylase type 1, MAX: myc-associated factor X.

Figure 6:

The outline of various transporter systems and receptors expressed on pheochromocytoma and paraganglioma cell membrane used for diagnosis and therapy of these tumors. Abbreviations: GLUT: glucose transporter system, LAT1: amino acid transporter system, NET: norepinephrine transporter system, SSTR2: somatostatin receptor type 2, DOTA-SSA: DOTA somatostatin analog, AACD: amino acid decarboxylase, HK: hexokinase, ¹⁸F-FDG-6P: ¹⁸F-FDG 6 phosphate, abbreviation for other specific radionuclides are explained in the main text.