Special Issue "Pheochromocytoma (PHEO) and Paraganglioma (PGL)"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: 31 March 2019

Special Issue Editors

Guest Editor
Prof. Karel Pacak

Senior Investigator, Chief, Section on Medical Neuroendocrinology, Head, Developmental Endocrine Oncology and Genetics Affinity Group. Eunice Kennedy Shriver NICHD, NIH, Building 10, CRC, Room 1E-3140, 10 Center Drive MSC-1109, Bethesda, Maryland 20892-1109 USA
Website | E-Mail
Interests: genetics; biochemistry; metabolomics; neuroendocrine tumors; paragangliomas; pheochromocytomas; oncotherapy
Guest Editor
Prof. David Taïeb

Department of Nuclear Medicine, La Timone University Hospital, European Center for Research in Medical Imaging, Aix-Marseille University, Marseille, France
Website | E-Mail
Interests: nuclear imaging; theranostics; neuroendocrine tumors; paragangliomas; pheochromocytomas; modeling; metabolomics

Special Issue Information

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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Published Papers (7 papers)

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Research

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Open AccessArticle Catecholamines Induce Left Ventricular Subclinical Systolic Dysfunction: A Speckle-Tracking Echocardiography Study
Cancers 2019, 11(3), 318; https://doi.org/10.3390/cancers11030318
Received: 9 January 2019 / Revised: 24 February 2019 / Accepted: 28 February 2019 / Published: 6 March 2019
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Abstract
Background: Pheochromocytomas (PHEO) are tumors arising from chromaffin cells from the adrenal medulla, having the ability to produce, metabolize and secrete catecholamines. The overproduction of catecholamines leads by many mechanisms to the impairment in the left ventricle (LV) function, however, endocardial measurement [...] Read more.
Background: Pheochromocytomas (PHEO) are tumors arising from chromaffin cells from the adrenal medulla, having the ability to produce, metabolize and secrete catecholamines. The overproduction of catecholamines leads by many mechanisms to the impairment in the left ventricle (LV) function, however, endocardial measurement of systolic function did not find any differences between patients with PHEO and essential hypertension (EH). The aim of the study was to investigate whether global longitudinal strain (GLS) derived from speckle-tracking echocardiography can detect catecholamine-induced subclinical impairments in systolic function. Methods: We analyzed 17 patients (10 females and seven males) with PHEO and 18 patients (nine females and nine males) with EH. The groups did not differ in age or in 24-h blood pressure values. Results: The patients with PHEO did not differ in echocardiographic parameters including LV ejection fraction compared to the EH patients (0.69 ± 0.04 vs. 0.71 ± 0.05; NS), nevertheless, in spackle-tracking analysis, the patients with PHEO displayed significantly lower GLS than the EH patients (−14.8 ± 1.5 vs. −17.8 ± 1.7; p < 0.001). Conclusions: Patients with PHEO have a lower magnitude of GLS than the patients with EH, suggesting that catecholamines induce a subclinical decline in LV systolic function. Full article
(This article belongs to the Special Issue Pheochromocytoma (PHEO) and Paraganglioma (PGL))
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Open AccessArticle Efficacy and Safety of Ablative Therapy in the Treatment of Patients with Metastatic Pheochromocytoma and Paraganglioma
Cancers 2019, 11(2), 195; https://doi.org/10.3390/cancers11020195
Received: 12 January 2019 / Revised: 3 February 2019 / Accepted: 5 February 2019 / Published: 7 February 2019
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Abstract
Metastatic pheochromocytoma and paraganglioma (PPGL) are incurable neuroendocrine tumors. The goals of treatment include palliating symptoms and reducing tumor burden. Little is known about the use of radiofrequency ablation (RFA), cryoablation (CRYO), and percutaneous ethanol injection (PEI) to treat metastatic PPGL. We performed [...] Read more.
Metastatic pheochromocytoma and paraganglioma (PPGL) are incurable neuroendocrine tumors. The goals of treatment include palliating symptoms and reducing tumor burden. Little is known about the use of radiofrequency ablation (RFA), cryoablation (CRYO), and percutaneous ethanol injection (PEI) to treat metastatic PPGL. We performed a retrospective study of patients age 17 years and older with metastatic PPGL who were treated with ablative therapy at Mayo Clinic, USA, between June 14, 1999 and November 14, 2017. Our outcomes measures were radiographic response, procedure-related complications, and symptomatic improvement. Thirty-one patients with metastatic PPGL had 123 lesions treated during 42 RFA, 23 CRYO, and 4 PEI procedures. The median duration of follow-up was 60 months (range, 0–163 months) for non-deceased patients. Radiographic local control was achieved in 69/80 (86%) lesions. Improvement in metastasis-related pain or symptoms of catecholamine excess was achieved in 12/13 (92%) procedures. Thirty-three (67%) procedures had no known complications. Clavien-Dindo Grade I, II, IV, and V complications occurred after 7 (14%), 7 (14%), 1 (2%), and 1 (2%) of the procedures, respectively. In patients with metastatic PPGL, ablative therapy can effectively achieve local control and palliate symptoms. Full article
(This article belongs to the Special Issue Pheochromocytoma (PHEO) and Paraganglioma (PGL))
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Open AccessArticle Increased Mortality in SDHB but Not in SDHD Pathogenic Variant Carriers
Cancers 2019, 11(1), 103; https://doi.org/10.3390/cancers11010103
Received: 17 December 2018 / Revised: 11 January 2019 / Accepted: 13 January 2019 / Published: 17 January 2019
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Abstract
Germline mutations in succinate dehydrogenase subunit B and D (SDHB and SDHD) are predisposed to hereditary paraganglioma (PGL) and pheochromocytoma (PHEO). The phenotype of pathogenic variants varies according to the causative gene. In this retrospective study, we estimate the mortality of [...] Read more.
Germline mutations in succinate dehydrogenase subunit B and D (SDHB and SDHD) are predisposed to hereditary paraganglioma (PGL) and pheochromocytoma (PHEO). The phenotype of pathogenic variants varies according to the causative gene. In this retrospective study, we estimate the mortality of a nationwide cohort of SDHB variant carriers and that of a large cohort of SDHD variant carriers and compare it to the mortality of a matched cohort of the general Dutch population. A total of 192 SDHB variant carriers and 232 SDHD variant carriers were included in this study. The Standard Mortality Ratio (SMR) for SDHB mutation carriers was 1.89, increasing to 2.88 in carriers affected by PGL. For SDHD variant carriers the SMR was 0.93 and 1.06 in affected carriers. Compared to the general population, mortality seems to be increased in SDHB variant carriers, especially in those affected by PGL. In SDHD variant carriers, the mortality is comparable to that of the general Dutch population, even if they are affected by PGL. This insight emphasizes the significance of DNA-testing in all PGL and PHEO patients, since different clinical risks may warrant gene-specific management strategies. Full article
(This article belongs to the Special Issue Pheochromocytoma (PHEO) and Paraganglioma (PGL))
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Open AccessArticle 18F-FDOPA PET/CT Combined with MRI for Gross Tumor Volume Delineation in Patients with Skull Base Paraganglioma
Received: 15 November 2018 / Revised: 30 December 2018 / Accepted: 2 January 2019 / Published: 8 January 2019
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Abstract
In this simulation study, we assessed differences in gross tumor volume (GTV) in a series of skull base paragangliomas (SBPGLs) using magnetic resonance imaging (MRI), 18F-dihydroxyphenylalanine (18F-FDOPA) combined positron emission tomography/computed tomography (PET/CT), and 18F-FDOPA PET/MRI images obtained by [...] Read more.
In this simulation study, we assessed differences in gross tumor volume (GTV) in a series of skull base paragangliomas (SBPGLs) using magnetic resonance imaging (MRI), 18F-dihydroxyphenylalanine (18F-FDOPA) combined positron emission tomography/computed tomography (PET/CT), and 18F-FDOPA PET/MRI images obtained by rigid alignment of PET and MRI. GTV was delineated in 16 patients with SBPGLs on MRI (GTVMRI), 18F-FDOPA PET/CT (GTVPET), and combined PET/MRI (GTVPET/MRI). GTVPET/MRI was the union of GTVMRI and GTVPET after visual adjustment. Three observers delineated GTVMRI and GTVPET/MRI independently. Excellent interobserver reproducibility was found for both GTVMRI and GTVPET/MRI. GTVPET and GTVMRI were not significantly different. However, there was some spatial difference between the locations of GTVMRI, GTVPET, and GTVPET/MRI. The Dice similarity coefficient median value was 0.4 between PET/CT and MRI, and 0.8 between MRI and PET/MRI. The combined use of PET/MRI produced a larger GTV than MRI alone. Nevertheless, both the target-delivered dose and organs-at-risk conservancy were respected when treatment was planned on the PET/MRI-matched data set. Future integration of 18F-FDOPA PET/CT into clinical practice will be necessary to evaluate the influence of this diagnostic modality on SBPGL therapeutic management. If the clinical utility of 18F-FDOPA PET/CT and/or PET/MRI is confirmed, GTVPET/MRI should be considered for tailored radiotherapy planning in patients with SBPGL. Full article
(This article belongs to the Special Issue Pheochromocytoma (PHEO) and Paraganglioma (PGL))
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Open AccessArticle RNA-Sequencing Analysis of Adrenocortical Carcinoma, Pheochromocytoma and Paraganglioma from a Pan-Cancer Perspective
Cancers 2018, 10(12), 518; https://doi.org/10.3390/cancers10120518
Received: 30 October 2018 / Revised: 11 December 2018 / Accepted: 13 December 2018 / Published: 15 December 2018
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Abstract
Adrenocortical carcinoma (ACC) and pheochromocytoma and paraganglioma (PPGL) are defined by clinicopathological criteria and can be further sub-divided based on different molecular features. Whether differences between these molecular subgroups are significant enough to re-challenge their current clinicopathological classification is currently unknown. It is [...] Read more.
Adrenocortical carcinoma (ACC) and pheochromocytoma and paraganglioma (PPGL) are defined by clinicopathological criteria and can be further sub-divided based on different molecular features. Whether differences between these molecular subgroups are significant enough to re-challenge their current clinicopathological classification is currently unknown. It is also not fully understood to which other cancers ACC and PPGL show similarity to. To address these questions, we included recent RNA-Seq data from the Cancer Genome Atlas (TCGA) and Therapeutically Applicable Research to Generate Effective Treatments (TARGET) datasets. Two bioinformatics pipelines were used for unsupervised clustering and principal components analysis. Results were validated using consensus clustering model and interpreted according to previous pan-cancer experiments. Two datasets consisting of 3319 tumors from 35 disease categories were studied. Consistent with the current classification, ACCs clustered as a homogenous group in a pan-cancer context. It also clustered close to neural crest derived tumors, including gliomas, neuroblastomas, pancreatic neuroendocrine tumors, and PPGLs. Contrary, some PPGLs mixed with pancreatic neuroendocrine tumors or neuroblastomas. Thus, our unbiased gene-expression analysis of PPGL did not overlap with their current clinicopathological classification. These results emphasize some importances of the shared embryological origin of these tumors, all either related or close to neural crest tumors, and opens for investigation of a complementary categorization based on gene-expression features. Full article
(This article belongs to the Special Issue Pheochromocytoma (PHEO) and Paraganglioma (PGL))
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Review

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Open AccessReview A Developmental Perspective on Paragangliar Tumorigenesis
Cancers 2019, 11(3), 273; https://doi.org/10.3390/cancers11030273
Received: 30 January 2019 / Revised: 20 February 2019 / Accepted: 21 February 2019 / Published: 26 February 2019
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Abstract
In this review, we propose that paraganglioma is a fundamentally organized, albeit aberrant, tissue composed of neoplastic vascular and neural cell types that share a common origin from a multipotent mesenchymal-like stem/progenitor cell. This view is consistent with the pseudohypoxic footprint implicated in [...] Read more.
In this review, we propose that paraganglioma is a fundamentally organized, albeit aberrant, tissue composed of neoplastic vascular and neural cell types that share a common origin from a multipotent mesenchymal-like stem/progenitor cell. This view is consistent with the pseudohypoxic footprint implicated in the molecular pathogenesis of the disease, is in harmony with the neural crest origin of the paraganglia, and is strongly supported by the physiological model of carotid body hyperplasia. Our immunomorphological and molecular studies of head and neck paragangliomas demonstrate in all cases relationships between the vascular and the neural tumor compartments, that share mesenchymal and immature vasculo-neural markers, conserved in derived cell cultures. This immature, multipotent phenotype is supported by constitutive amplification of NOTCH signaling genes and by loss of the microRNA-200s and -34s, which control NOTCH1, ZEB1, and PDGFRA in head and neck paraganglioma cells. Importantly, the neuroepithelial component is distinguished by extreme mitochondrial alterations, associated with collapse of the ΔΨm. Finally, our xenograft models of head and neck paraganglioma demonstrate that mesenchymal-like cells first give rise to a vasculo-angiogenic network, and then self-organize into neuroepithelial-like clusters, a process inhibited by treatment with imatinib. Full article
(This article belongs to the Special Issue Pheochromocytoma (PHEO) and Paraganglioma (PGL))
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Open AccessReview The Value of Histological Algorithms to Predict the Malignancy Potential of Pheochromocytomas and Abdominal Paragangliomas—A Meta-Analysis and Systematic Review of the Literature
Cancers 2019, 11(2), 225; https://doi.org/10.3390/cancers11020225
Received: 21 January 2019 / Revised: 11 February 2019 / Accepted: 13 February 2019 / Published: 15 February 2019
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Abstract
Pheochromocytomas (PCCs) and abdominal paragangliomas (PGLs), collectively abbreviated PPGLs, are neuroendocrine tumors of the adrenal medulla and paraganglia, respectively. These tumors exhibit malignant potential but seldom display evidence of metastatic spread, the latter being the only widely accepted evidence of malignancy. To counter [...] Read more.
Pheochromocytomas (PCCs) and abdominal paragangliomas (PGLs), collectively abbreviated PPGLs, are neuroendocrine tumors of the adrenal medulla and paraganglia, respectively. These tumors exhibit malignant potential but seldom display evidence of metastatic spread, the latter being the only widely accepted evidence of malignancy. To counter this, pre-defined histological algorithms have been suggested to stratify the risk of malignancy: Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) and the Grading system for Adrenal Pheochromocytoma and Paraganglioma (GAPP). The PASS algorithm was originally intended for PCCs whereas the GAPP model is proposed for stratification of both PCCs and PGLs. In parallel, advances in terms of coupling overtly malignant PPGLs to the underlying molecular genetics have been made, but there is yet no combined risk stratification model based on histology and the overall mutational profile of the tumor. In this review, we systematically meta-analyzed previously reported cohorts using the PASS and GAPP algorithms and acknowledge a “rule-out” way of approaching these stratification models rather than a classical “rule-in” strategy. Moreover, the current genetic panorama regarding possible molecular adjunct markers for PPGL malignancy is reviewed. A combined histological and genetic approach will be needed to fully elucidate the malignant potential of these tumors. Full article
(This article belongs to the Special Issue Pheochromocytoma (PHEO) and Paraganglioma (PGL))
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