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Endocrine-related Cancer Jan 2023Mitochondrial DNA (mtDNA) alterations have been reported in different types of cancers and are suggested to play important roles in cancer development and metastasis.... (Review)
Review
Mitochondrial DNA (mtDNA) alterations have been reported in different types of cancers and are suggested to play important roles in cancer development and metastasis. However, there is little information about its involvement in pheochromocytomas and paragangliomas (PCCs/PGLs) formation. PCCs and PGLs are rare endocrine tumors of the chromaffin cells in the adrenal medulla and extra-adrenal paraganglia that can synthesize and secrete catecholamines. Over the last 3 decades, the genetic background of about 60% of PCCs/PGLs involving nuclear DNA alterations has been determined. Recently, a study showed that mitochondrial alterations can be found in around 17% of the remaining PCCs/PGLs. In this review, we summarize recent knowledge regarding both nuclear and mitochondrial alterations and their involvement in PCCs/PGLs. We also provide brief insights into the genetics and the molecular pathways associated with PCCs/PGLs and potential therapeutical targets.
Topics: Humans; DNA, Mitochondrial
PubMed: 36219865
DOI: 10.1530/ERC-22-0217 -
Frontiers in Endocrinology 2020Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors originating from chromaffin cells in the adrenal medulla (PCCs) or extra-adrenal sympathetic... (Review)
Review
Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors originating from chromaffin cells in the adrenal medulla (PCCs) or extra-adrenal sympathetic or parasympathetic paraganglia (PGLs). About 40% of PPGLs result from germline mutations and therefore they are highly inheritable. Although dysfunction of any one of a panel of more than 20 genes can lead to PPGLs, mutations in genes involved in the VHL/HIF axis including , , , and are more frequently found in PPGLs. Multiple lines of evidence indicate that pseudohypoxia plays a crucial role in the tumorigenesis of PPGLs, and therefore PPGLs are also known as metabolic diseases. However, the interplay between VHL/HIF-mediated pseudohypoxia and metabolic disorder in PPGLs cells is not well-defined. In this review, we will first discuss the VHL/HIF axis and genetic alterations in this axis. Then, we will dissect the underlying mechanisms in VHL/HIF axis-driven PPGL pathogenesis, with special attention paid to the interplay between the VHL/HIF axis and cancer cell metabolism. Finally, we will summarize the currently available compounds/drugs targeting this axis which could be potentially used as PPGLs treatment, as well as their underlying pharmacological mechanisms. The overall goal of this review is to better understand the role of VHL/HIF axis in PPGLs development, to establish more accurate tools in PPGLs diagnosis, and to pave the road toward efficacious therapeutics against metastatic PPGLs.
Topics: Adrenal Gland Neoplasms; Animals; Antineoplastic Agents; Apoptosis Regulatory Proteins; Basic Helix-Loop-Helix Transcription Factors; Chromaffin Cells; Germ-Line Mutation; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Pheochromocytoma; Protein Kinase Inhibitors; Repressor Proteins; Von Hippel-Lindau Tumor Suppressor Protein
PubMed: 33329393
DOI: 10.3389/fendo.2020.586857 -
Autopsy & Case Reports 2021Paragangliomas are rare, encapsulated, benign neuroendocrine tumors that can arise from the adrenal medulla or extra-adrenal paraganglia. Extra-adrenal paragangliomas...
Paragangliomas are rare, encapsulated, benign neuroendocrine tumors that can arise from the adrenal medulla or extra-adrenal paraganglia. Extra-adrenal paragangliomas may develop a gangliocytic component with ganglion cells (Gangliocytic paragangliomas). Nearly 25%of cauda equina paragangliomas are gangliocytic paragangliomas. Here, we describe the case of a 35-year-old male who presented with weakness of both lower limbs over the last two months. Radiological findings were suggestive of myxopapillary ependymoma. However, the histopathological examination revealed a tumor with cells arranged in sheets, papillae, lobules, and around vessels forming pseudo rosettes. Ganglion cells were seen in small groups and, also singly. Tumor cells were immunopositive for chromogranin, synaptophysin, and S-100. Ganglion cells were immunopositive for synaptophysin, NSE, and NFP. A final histological diagnosis of Gangliocytic paraganglioma (WHO grade I) was made. To date, only nine gangliocytic paraganglioma cases have been previously reported, and to the best of our knowledge, this is the largest gangliocytic paraganglioma.
PubMed: 34307231
DOI: 10.4322/acr.2021.277 -
The Canadian Journal of Cardiology May 2020The genetic architecture of blood pressure (BP) now includes more than 30 genes, with rare mutations resulting in inherited forms of hypertension or hypotension, and... (Review)
Review
The genetic architecture of blood pressure (BP) now includes more than 30 genes, with rare mutations resulting in inherited forms of hypertension or hypotension, and 1477 common single-nucleotide polymorphisms (SNPs). These signify the heterogeneity of the BP phenotype and support the mosaic theory of hypertension. The majority of monogenic syndromes involve the renin-angiotensin-aldosterone system and the adrenal glucocorticoid pathway, and a smaller fraction are due to rare neuroendocrine tumours of the adrenal glands and the sympathetic and parasympathetic paraganglia. Somatic mutations in genes coding for ion channels (KCNJ5 and CACNA1D) and adenosine triphosphatases (ATP1A1 and ATP2B3) highlight the central role of calcium signalling in autonomous aldosterone production by the adrenal gland. The per-SNP BP effect is small for SNPs according to genome-wide association studies (GWAS), and all of the GWAS-identified BP SNPs explain ∼ 27% of the 30%-50% estimated heritability of BP. Uromodulin is a novel pathway identified by GWAS, and it has now progressed to a genotype-directed clinical trial. The majority of the GWAS-identified BP SNPs show pleiotropic associations, and unravelling those signals and underpinning biological pathways offers potential opportunities for drug repurposing. The GWAS signals are predominantly from Europe-centric studies with other ancestries underrepresented, however, limiting the generalisability of the findings. In this review, we leverage the burgeoning list of polygenic and monogenic variants associated with BP regulation along with phenome-wide studies in the context of the mosaic theory of hypertension, and we explore potential translational aspects that underlie different hypertension subtypes.
Topics: Blood Pressure; Genetic Pleiotropy; Genetic Predisposition to Disease; Genome-Wide Association Study; Genomics; Humans; Hypertension; Microfilament Proteins; Multifactorial Inheritance; Pharmacogenetics; Polymorphism, Single Nucleotide; Uromodulin
PubMed: 32389342
DOI: 10.1016/j.cjca.2020.03.001 -
BMC Medical Genomics Sep 2020Carotid and vagal paragangliomas (CPGLs and VPGLs) are rare neoplasms that arise from the paraganglia located at the bifurcation of carotid arteries and vagal trunk,...
BACKGROUND
Carotid and vagal paragangliomas (CPGLs and VPGLs) are rare neoplasms that arise from the paraganglia located at the bifurcation of carotid arteries and vagal trunk, respectively. Both tumors can occur jointly as multiple paragangliomas accounting for approximately 10 to 20% of all head and neck paragangliomas. However, molecular and genetic mechanisms underlying the pathogenesis of multiple paragangliomas remain elusive.
CASE PRESENTATION
We report a case of multiple paragangliomas in a patient, manifesting as bilateral CPGL and unilateral VPGL. Tumors were revealed via computed tomography and ultrasound study and were resected in two subsequent surgeries. Both CPGLs and VPGL were subjected to immunostaining for succinate dehydrogenase (SDH) subunits and exome analysis. A likely pathogenic germline variant in the SDHD gene was indicated, while likely pathogenic somatic variants differed among the tumors.
CONCLUSIONS
The identified germline variant in the SDHD gene seems to be a driver in the development of multiple paragangliomas. However, different spectra of somatic variants identified in each tumor indicate individual molecular mechanisms underlying their pathogenesis.
Topics: Carotid Artery Diseases; Cranial Nerve Neoplasms; Female; Humans; Middle Aged; Neoplasms, Multiple Primary; Paraganglioma; Succinate Dehydrogenase; Vagus Nerve Diseases; Vascular Neoplasms
PubMed: 32948182
DOI: 10.1186/s12920-020-00789-8 -
Diagnostics (Basel, Switzerland) Jul 2022Paragangliomas are rare, non-epithelial neuroendocrine neoplasms originating in paraganglia, for instance the adrenal medulla, or at extra-adrenal locations. The aim of... (Review)
Review
Paragangliomas are rare, non-epithelial neuroendocrine neoplasms originating in paraganglia, for instance the adrenal medulla, or at extra-adrenal locations. The aim of this study was to review the literature regarding abdominal extra-adrenal paragangliomas diagnosed pre-operatively with fine-needle biopsy (FNA and/or FNB). The PubMed database was searched to identify such cases, using a specific algorithm and inclusion/exclusion criteria. An unpublished case from our practice was also added to the rest of the data, resulting in a total of 36 cases for analysis. Overall, 24 (67%) lesions were found in females, whereas 12 (33%) in males. Most (21/36; 58.33%) were identified around and/or within the pancreatic parenchyma. FNA and/or FNB reached or suggested a paraganglioma diagnosis in 17/36 cases (47.22%). Of the preoperative misdiagnoses, the most common was an epithelial neuroendocrine tumor (NET). Regarding follow-up, most patients were alive with no reported recurrence; however, 5/36 patients exhibited a recurrence or a widespread disease, whereas one patient died 48 months following her diagnosis. In two patients, transient hypertension was reported during the EUS-FNA procedure. In conclusion, this study showed that the preoperative diagnosis of these lesions is feasible and, while diagnostic pitfalls exist, they could significantly be avoided with the application of immunochemistry.
PubMed: 36010170
DOI: 10.3390/diagnostics12081819 -
Journal of Cardiothoracic Surgery May 2020Paragangliomas are rare endocrine tumors that arise from the extra-adrenal autonomic paraganglia and sympathetic paragangliomas usually secret catecholamines and are...
INTRODUCTION
Paragangliomas are rare endocrine tumors that arise from the extra-adrenal autonomic paraganglia and sympathetic paragangliomas usually secret catecholamines and are located in the sympathetic paravertebral ganglia of thorax, abdomen, and pelvis. In contrast, most parasympathetic paragangliomas are nonfunctional and located along the glossopharyngeal and vagal nerves in the neck and at the base of the skull. Such neoplasms, although rare, are clinically important because they may recur after surgical resection and 10% of them give rise to metastases causing death with the lymphatic nodes, bones, liver, and lungs being the most common locations.
CASE PRESENTATION
We present a case of a 26-year-old male patient that was diagnosed with paraganglioma of the right-frontal lobe infiltrating the falx and frontal bone which was diagnosed after suffering from a headache and abnormal vision. On initial work-up he was found to have right pulmonary nodules that increased in size after follow up and other nodules appeared in the contralateral lung. He underwent subtotal resection of the brain tumor and complete resection of the bilateral pulmonary nodules.
CONCLUSION
To our knowledge, paraganglioma is considered to be a rare entity in the central nervous system with very few cases being reported in the supratentorial region and no cases were reported of metastatic such paraganglioma to the lung.
Topics: Adult; Brain; Humans; Lung Neoplasms; Magnetic Resonance Imaging; Male; Multiple Pulmonary Nodules; Neoplasm Metastasis; Neoplasm Recurrence, Local; Paraganglioma; Tomography, X-Ray Computed; Treatment Outcome
PubMed: 32393294
DOI: 10.1186/s13019-020-01113-2 -
Radiology. Imaging Cancer May 2022Paragangliomas are neuroendocrine tumors that derive from paraganglia of the autonomic nervous system, with the majority of parasympathetic paragangliomas arising in the... (Review)
Review
Paragangliomas are neuroendocrine tumors that derive from paraganglia of the autonomic nervous system, with the majority of parasympathetic paragangliomas arising in the head and neck. More than one-third of all paragangliomas are hereditary, reflecting the strong genetic predisposition of these tumors. The molecular basis of paragangliomas has been investigated extensively in the past couple of decades, leading to the discovery of several molecular clusters and more than 20 well-characterized driver genes (somatic and hereditary), which are more than are known for any other endocrine tumor. Head and neck paragangliomas are largely related to the pseudohypoxia cluster and have been previously excluded from most molecular profiling studies. This review article introduces the molecular classification of paragangliomas, with a focus on head and neck paragangliomas, and discusses its impact on the management of these tumors. Genetic testing is now recommended for all patients with paragangliomas to provide screening and surveillance recommendations for patients and relatives. While CT and MRI provide excellent anatomic characterization of paragangliomas, gallium 68 tetraazacyclododecane tetraacetic acid-octreotate (ie, Ga-DOTATATE) has superior sensitivity and is recommended as first-line imaging in patients with head and neck paragangliomas with concern for multifocal and metastatic disease, patients with known multifocal and metastatic disease, and in candidates for targeted peptide-receptor therapy. Molecular Imaging, MR Perfusion, MR Spectroscopy, Neuro-Oncology, PET/CT, SPECT/CT, Head/Neck, Genetic Defects © RSNA, 2022.
Topics: Head and Neck Neoplasms; Humans; Magnetic Resonance Imaging; Paraganglioma; Paraganglioma, Extra-Adrenal; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Radionuclide Imaging
PubMed: 35549357
DOI: 10.1148/rycan.210088 -
Frontiers in Veterinary Science 2023Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors arising from the chromaffin cells in the adrenal medulla and extra-adrenal paraganglia,...
Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors arising from the chromaffin cells in the adrenal medulla and extra-adrenal paraganglia, respectively. Local invasion, concurrent disorders, and metastases prevent surgical removal, which is the most effective treatment to date. Given the current lack of effective medical treatment, there is a need for novel therapeutic strategies. To identify druggable pathways driving PPGL development, we performed RNA sequencing on PPGLs ( = 19) and normal adrenal medullas (NAMs; = 10) of dogs. Principal component analysis (PCA) revealed that PPGLs clearly clustered apart from NAMs. In total, 4,218 genes were differentially expressed between PPGLs and NAMs. Of these, 232 had a log fold change of >3 or < -3, of which 149 were upregulated in PPGLs, and 83 were downregulated. Compared with NAMs, PPGLs had increased expression of genes related to the cell cycle, tumor development, progression and metastasis, hypoxia and angiogenesis, and the Wnt signaling pathway, and decreased expression of genes related to adrenal steroidogenesis. Our data revealed several overexpressed genes that could provide targets for novel therapeutics, such as Ret Proto-Oncogene (), Dopamine Receptor D2 (), and Secreted Frizzled Related Protein 2 (). Based on the PCA, PPGLs were classified into 2 groups, of which group 1 had significantly higher Ki67 scores ( = 0.035) and shorter survival times ( = 0.04) than group 2. Increased expression of 1 of the differentially expressed genes between group 1 and 2, pleiotrophin (), appeared to correlate with a more aggressive tumor phenotype. This study has shed light on the transcriptomic profile of canine PPGL, yielding new insights into the pathogenesis of these tumors in dogs, and revealed potential novel targets for therapy. In addition, we identified 2 transcriptionally distinct groups of PPGLs that had significantly different survival times.
PubMed: 37691636
DOI: 10.3389/fvets.2023.1155804