Dear Colleagues,

Pheochromocytomas and paragangliomas (collectively termed PPGLs), are rare neuroendocrine tumors originating from chromaffin cells in the adrenal medulla or paraganglia outside the adrenal medulla, respectively. Uniquely, these tumors secrete catecholamines, mainly norepinephrine and epinephrine, that profoundly affect cardiovascular, gastrointestinal, and to lesser extents, other systems. Thus, if these tumors remain unrecognized, they pose a severe threat to a patient by potentially causing sudden death due to lethal arrhythmia, myocardial infarction, and stroke. Therefore, all attempts should be made to diagnose and treat these tumors early, before they strike a patient or become metastatic.

Recently, there has been significant progress in the genetics of these tumors. New genes—HIF2A, H-RAS, FH, MDH2, EGLN2, IRP1, DNMT3A, MERTK, MET, and H3F3A—have been discovered, although all are found much less frequently (altogether in about 10% of these tumors) than other previously described pheochromocytoma susceptibility genes (e.g. RET, NF1, VHL, SDHA/B/C/D). About two years ago, we classified these tumors into two main clusters/subtypes (hypoxia and kinase signaling), and now, thanks to The Cancer Genome Atlas (TCGA) initiative, we have added two additional clusters/subtypes (wnt signaling and cortical admixture), further reflecting a more precise genetic classification and enabling us to potentially better predict clinical behavior. TCGA initiative also concluded that 69% of PPGLs had driver alterations, which were either germline or somatic mutations or somatic gene fusions, the latter described for the first time. These and other findings facilitated new comprehensive efforts to accelerate our understanding of the molecular basis of metastatic PPGLs through the application of state-of-the art genome analysis technologies tightly linked to the most updated bioinformatics tools. Very recently, metabolomic profiles were also introduced for the diagnostic evaluation of these tumors and for the indentification of new genes. For example, magnetic resonance spectroscopy now provides the opportunity to characterize these tumors from a whole body perspective and could potentially help monitor oncometabolites during therapies and follow-up.

Multimodality–multiparametric imaging has emerged at the forefront of personalized medicine. The use of molecular imaging, particularly positron emission tomography compounds, in the localization of these tumors has been successfully expanded. Specifically, [⁶⁸Ga]-DOTATATE PET/CT has become the best available imaging modality for metastatic and head and neck PPGLs with FDA approval in 2018. These results prompted the introduction of peptide receptor radionuclide therapy using radiolabeled somatostatin analogues (both agonists and antagonists, ¹⁷⁷Lu-DOTATATE /Lutathera/ and ¹⁷⁷Lu-DOTA-JR11, respectively) for these tumors. It is also expected that the use of alpha-particle emitters be transferred to PPGL patients soon.

This series of articles is presented by an international team of experts in these tumors who enriched every part of this series. Without their dedication, deep knowledge and understanding of these tumors, participation in international studies and projects, and commitment to future work, this would not be possible. This collaborative effort reflects the scope and spirit of these issues, nicely blending current and future genetic, diagnostic, therapeutic, and preventive approaches to PPGLs. And although therapeutic and preventive options for PPGLs, especially metastatic disease, are still in their infancy, several new studies are now in progress or planned. Personalized treatment and care of patients with PPGLs, including the use of predictive biomarkers for the presence of these tumors or their metastatic spread, manipulation of the immune system to fight these tumors, understanding host and environmental factors, and the use of artificial intelligence to classify information will become a reality in the near future, with the potential to transform the lives of patients with these tumors. 

Let us conclude with a quotation from Dr. William Mayo : « The glory of medicine is that it is constantly moving forward, that there is always more to learn. »

Prof. Karel Pacak
Prof. David Taïeb
Guest Editors

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