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. 2021 Mar 25;32(2):228–244. doi: 10.1007/s12022-021-09675-0

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© The Author(s) 2021

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 3 — Pseudohypoxia-driven PPGLs. The pseudo-hypoxia cluster of PPGL is traditionally associated to worse clinical outcome, but a closer look at the sub-stratification of this cluster reveals an association between mutations in genes implicated in the regulation of the tricarboxylic acid (TCA) cycle and increased metastatic potential, as opposed to TCA cycle non-aberrant PPGLs within the same cluster. While both subgroups activate the HIF signaling pathway, TCA cycle mutated tumors also exhibit epigenetic dysregulation as a consequence of the accumulation of onco-metabolites (fumarate, succinate, and α-ketoglutarate (α-KG) derivatives. The risk of metastatic events among patients with pseudohypoxia-driven PPGLs is much higher in TCA cycle aberrant cases (40.5% of patients) than in TCA cycle non-aberrant cases (11.2% of patients) [5]