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Oncotarget Apr 2017Paragangliomas/pheochromocytomas comprise rare tumors that arise from the extra-adrenal paraganglia, with an incidence of about 2 to 8 per million people each year.... (Review)
Review
Paragangliomas/pheochromocytomas comprise rare tumors that arise from the extra-adrenal paraganglia, with an incidence of about 2 to 8 per million people each year. Approximately 40% of cases are due to genetic mutations in at least one out of more than 30 causative genes. About 25-30% of pheochromocytomas/paragangliomas develop under the conditions of a hereditary tumor syndrome a third of which are caused by mutations in the VHL gene. Together, the gene mutations in this disorder have implicated multiple processes including signaling pathways, translation initiation, hypoxia regulation, protein synthesis, differentiation, survival, proliferation, and cell growth. The present review contemplates the mutations associated with the development of pheochromocytomas/paragangliomas and their potential to serve as specific markers of these tumors and their progression. These data will improve our understanding of the pathogenesis of these tumors and likely reveal certain features that may be useful for early diagnostics, malignancy prognostics, and the determination of new targets for disease therapeutics.
Topics: Adrenal Gland Neoplasms; Animals; Biomarkers, Tumor; Cell Transformation, Neoplastic; Gene Expression Regulation, Neoplastic; Genetic Variation; Humans; Paraganglioma; Pheochromocytoma; Signal Transduction
PubMed: 28187001
DOI: 10.18632/oncotarget.15201 -
Frontiers in Endocrinology 2021Neuroendocrine tumors overexpress somatostatin receptors, which serve as important and unique therapeutic targets for well-differentiated advanced disease. This... (Review)
Review
Neuroendocrine tumors overexpress somatostatin receptors, which serve as important and unique therapeutic targets for well-differentiated advanced disease. This overexpression is a well-established finding in gastroenteropancreatic neuroendocrine tumors which has guided new medical therapies in the administration of somatostatin analogs, both "cold", particularly octreotide and lanreotide, and "hot" analogs, chelated to radiolabeled isotopes. The binding of these analogs to somatostatin receptors effectively suppresses excess hormone secretion and tumor cell proliferation, leading to stabilization, and in some cases, tumor shrinkage. Radioisotope-labeled somatostatin analogs are utilized for both tumor localization and peptide radionuclide therapy, with Ga-DOTATATE and Lu-DOTATATE respectively. Benign and malignant pheochromocytomas and paragangliomas also overexpress somatostatin receptors, irrespective of embryological origin. The pattern of somatostatin receptor overexpression is more prominent in gene mutation, which is more aggressive than other subgroups of this disease. While the Food and Drug Administration has approved the use of Ga-DOTATATE as a radiopharmaceutical for somatostatin receptor imaging, the use of its radiotherapeutic counterpart still needs approval beyond gastroenteropancreatic neuroendocrine tumors. Thus, patients with pheochromocytoma and paraganglioma, especially those with inoperable or metastatic diseases, depend on the clinical trials of somatostatin analogs. The review summarizes the advances in the utilization of somatostatin receptor for diagnostic and therapeutic approaches in the neuroendocrine tumor subset of pheochromocytoma and paraganglioma; we hope to provide a positive perspective in using these receptors as targets for treatment in this rare condition.
Topics: Adrenal Gland Neoplasms; Humans; Paraganglioma; Pheochromocytoma; Precision Medicine; Radiopharmaceuticals; Receptors, Somatostatin
PubMed: 33854479
DOI: 10.3389/fendo.2021.625312 -
Nature Communications Oct 2022Pheochromocytomas (PC) and paragangliomas (PG) are rare neuroendocrine tumors associated with autonomic nerves. Here we use single-nuclei RNA-seq and bulk-tissue...
Pheochromocytomas (PC) and paragangliomas (PG) are rare neuroendocrine tumors associated with autonomic nerves. Here we use single-nuclei RNA-seq and bulk-tissue gene-expression data to characterize the cellular composition of PCPG and normal adrenal tissues, refine tumor gene-expression subtypes and make clinical and genotypic associations. We confirm seven PCPG gene-expression subtypes with significant genotype and clinical associations. Tumors with mutations in VHL, SDH-encoding genes (SDHx) or MAML3-fusions are characterized by hypoxia-inducible factor signaling and neoangiogenesis. PCPG have few infiltrating lymphocytes but abundant macrophages. While neoplastic cells transcriptionally resemble mature chromaffin cells, early chromaffin and neuroblast markers are also features of some PCPG subtypes. The gene-expression profile of metastatic SDHx-related PCPG indicates these tumors have elevated cellular proliferation and a lower number of non-neoplastic Schwann-cell-like cells, while GPR139 is a potential theranostic target. Our findings therefore clarify the diverse transcriptional programs and cellular composition of PCPG and identify biomarkers of potential clinical significance.
Topics: Humans; Pheochromocytoma; Tumor Microenvironment; Paraganglioma; Adrenal Gland Neoplasms; Succinate Dehydrogenase
PubMed: 36271074
DOI: 10.1038/s41467-022-34011-3 -
Journal of Internal Medicine Dec 2016Pheochromocytoma and paraganglioma (PPGL) are rare diseases but are also amongst the most characterized tumour types. Hence, patients with PPGL have greatly benefited... (Review)
Review
Pheochromocytoma and paraganglioma (PPGL) are rare diseases but are also amongst the most characterized tumour types. Hence, patients with PPGL have greatly benefited from precision medicine for more than two decades. According to current molecular biology and genetics-based taxonomy, PPGL can be divided into three different clusters characterized by: Krebs cycle reprogramming with oncometabolite accumulation or depletion (group 1a); activation of the (pseudo)hypoxia signalling pathway with increased tumour cell proliferation, invasiveness and migration (group 1b); and aberrant kinase signalling causing a pro-mitogenic and anti-apoptotic state (group 2). Categorization into these clusters is highly dependent on mutation subtypes. At least 12 different syndromes with distinct genetic causes, phenotypes and outcomes have been described. Genetic screening tests have a documented benefit, as different PPGL syndromes require specific approaches for optimal diagnosis and localization of various syndrome-related tumours. Genotype-tailored treatment options, follow-up and preventive care are being investigated. Future new developments in precision medicine for PPGL will mainly focus on further identification of driver mechanisms behind both disease initiation and malignant progression. Identification of novel druggable targets and prospective validation of treatment options are eagerly awaited. To achieve these goals, we predict that collaborative large-scale studies will be needed: Pheochromocytoma may provide an example for developing precision medicine in orphan diseases that could ultimately aid in similar efforts for other rare conditions.
Topics: Adrenal Gland Neoplasms; Citric Acid Cycle; Humans; Paraganglioma; Pheochromocytoma; Polycythemia; Precision Medicine; Signal Transduction; Syndrome; von Hippel-Lindau Disease
PubMed: 27165774
DOI: 10.1111/joim.12507 -
Radiologia 2022Pheochromocytomas are adrenal paragangliomas. Potentially malignant, these tumors have a low incidence but clear importance. They can appear in various hereditary...
Pheochromocytomas are adrenal paragangliomas. Potentially malignant, these tumors have a low incidence but clear importance. They can appear in various hereditary syndromes, especially in von Hippel-Lindau syndrome, multiple endocrine neoplasia-2 (MEN2), and familial paraganglioma syndromes. In sporadic cases, underlying genetic alterations are often found, and these findings are changing our understanding of the disease. Although these tumors can manifest with a characteristic clinical presentation, in 13.1%-57.6% of cases, it is the radiologist who first suggests the diagnosis, indicating analyses for catecholamines or nuclear medicine examinations. Radiologists should suspect a pheochromocytoma on detection of a well-delimited adrenal mass with rapid, intense enhancement that typically shows cystic and hemorrhagic phenomena, high T2 signal intensity, and the absence of macroscopic or microscopic lipids. The behavior in diffusion-weighted imaging usually does not provide very useful information. Approximately one-third of lesions show late washout similar to that seen with adenomas on CT. Percutaneous puncture should be avoided to avoid the risk of unleashing a severe hypertensive crisis.
Topics: Adrenal Gland Neoplasms; Humans; Paraganglioma; Pheochromocytoma; Syndrome; von Hippel-Lindau Disease
PubMed: 36030082
DOI: 10.1016/j.rxeng.2022.07.002 -
Clinical Cancer Research : An Official... Oct 2016Dysregulated metabolism is one of the key characteristics of cancer cells. The most prominent alterations are present during regulation of cell respiration, which leads... (Review)
Review
Dysregulated metabolism is one of the key characteristics of cancer cells. The most prominent alterations are present during regulation of cell respiration, which leads to a switch from oxidative phosphorylation to aerobic glycolysis. This metabolic shift results in activation of numerous signaling and metabolic pathways supporting cell proliferation and survival. Recent progress in genetics and metabolomics has allowed us to take a closer look at the metabolic changes present in pheochromocytomas (PHEO) and paragangliomas (PGL). These neuroendocrine tumors often exhibit dysregulation of mitochondrial metabolism, which is driven by mutations in genes encoding Krebs cycle enzymes or by activation of hypoxia signaling. Present metabolic changes are involved in processes associated with tumorigenesis, invasiveness, metastasis, and resistance to various cancer therapies. In this review, we discuss the metabolic nature of PHEOs/PGLs and how unveiling the metabolic disturbances present in tumors could lead to identification of new biomarkers and personalized cancer therapies. Clin Cancer Res; 22(20); 5001-11. ©2016 AACR SEE ALL ARTICLES IN THIS CCR FOCUS SECTION, "ENDOCRINE CANCERS REVISING PARADIGMS".
Topics: Adrenal Gland Neoplasms; Cell Hypoxia; Citric Acid Cycle; Glutamine; Glycolysis; Humans; Mitochondria; Paraganglioma; Pheochromocytoma
PubMed: 27742786
DOI: 10.1158/1078-0432.CCR-16-0606 -
Endocrine Reviews Dec 2017A molecular biology-based taxonomy has been proposed for pheochromocytoma and paraganglioma (PPGL). Data from the Cancer Genome Atlas revealed clinically relevant... (Review)
Review
A molecular biology-based taxonomy has been proposed for pheochromocytoma and paraganglioma (PPGL). Data from the Cancer Genome Atlas revealed clinically relevant prognostic and predictive biomarkers and stratified PPGLs into three main clusters. Each subgroup has a distinct molecular-biochemical-imaging signature. Concurrently, new methods for biochemical analysis, functional imaging, and medical therapies have also become available. The research community now strives to match the cluster biomarkers with the best intervention. The concept of precision medicine has been long awaited and holds great promise for improved care. Here, we review the current and future PPGL classifications, with a focus on hereditary syndromes. We discuss the current strengths and shortcomings of precision medicine and suggest a condensed manual for diagnosis and treatment of both adult and pediatric patients with PPGL. Finally, we consider the future direction of this field, with a particular focus on how advanced molecular characterization of PPGL can improve a patient's outcome, including cures and, ultimately, disease prevention.
Topics: Adrenal Gland Neoplasms; Biomarkers, Tumor; Genetic Predisposition to Disease; Humans; Molecular Diagnostic Techniques; Mutation; Paraganglioma; Pheochromocytoma; Precision Medicine
PubMed: 28938417
DOI: 10.1210/er.2017-00062 -
Cell and Tissue Research May 2018Pheochromocytomas and their extra-adrenal counterpart paragangliomas (PGLs; together called PPGLs), belong to the family of neural crest-derived tumors. Given the... (Review)
Review
Pheochromocytomas and their extra-adrenal counterpart paragangliomas (PGLs; together called PPGLs), belong to the family of neural crest-derived tumors. Given the overexpression of a wide variety of specific targets in PPGLs, it seems that these tumors are optimally suited to be imaged by specific radiopharmaceuticals. Thus, theranostics approaches with somatostatin agonists and antagonists are rapidly evolving in the setting of these tumors and may be considered as the next step in the therapeutic arsenal of metastatic PPGLs.
Topics: Adrenal Gland Neoplasms; Humans; Molecular Imaging; Paraganglioma; Pheochromocytoma; Radiopharmaceuticals; Theranostic Nanomedicine
PubMed: 29450723
DOI: 10.1007/s00441-018-2791-4 -
The Journal of Clinical Endocrinology... Oct 2023
Topics: Humans; Pheochromocytoma; Prognosis; Neutrophils; Paraganglioma; Adrenal Gland Neoplasms
PubMed: 37011227
DOI: 10.1210/clinem/dgad192 -
Journal of the National Cancer Institute Jan 2022
Topics: Adrenal Gland Neoplasms; Electron Transport; Humans; Paraganglioma; Pheochromocytoma
PubMed: 34415349
DOI: 10.1093/jnci/djab160