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The International Journal of... May 2021Phaeochromocytomas and paragangliomas are rare neuroendocrine tumours. So far, over 20 causative genes have been identified, of which the most frequent and strongest... (Review)
Review
Phaeochromocytomas and paragangliomas are rare neuroendocrine tumours. So far, over 20 causative genes have been identified, of which the most frequent and strongest indicator for malignancies are mutations in succinate dehydrogenase subunit B. No curative therapy is available for patients with metastases resulting in poor prognosis. Therapy development has been hindered by lack of suitable model systems. The succinate dehydrogenase complex is located in the inner membrane of the mitochondria and plays a crucial role in the oxidative phosphorylation chain and the tricarboxylic acid-cycle. Succinate dehydrogenase deficiency results in accumulation of the oncometabolite succinate inducing hypoxia inducible factor stabilization, deoxyribonucleic acid and histone methylation inhibition, and impaired production of adenosine triphosphate. It remains unknown which combination of pathways and/or triggers are decisive for metastases development. In this review, the role of mitochondria in malignant succinate dehydrogenase subunit B-associated phaeochromocytomas and paragangliomas and implications for mitochondria as therapeutic target are discussed.
Topics: Adrenal Gland Neoplasms; Animals; Electron Transport Complex II; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Metabolism, Inborn Errors; Mitochondria; Mitochondrial Diseases; Mutation; Paraganglioma; Pheochromocytoma; Reactive Oxygen Species; Succinate Dehydrogenase
PubMed: 33609747
DOI: 10.1016/j.biocel.2021.105949 -
Journal of the American College of... Jul 2020Pheochromocytomas, arising from chromaffin cells, produce catecholamines, epinephrine and norepinephrine. The tumor biochemical phenotype is defined by which of these... (Review)
Review
Pheochromocytomas, arising from chromaffin cells, produce catecholamines, epinephrine and norepinephrine. The tumor biochemical phenotype is defined by which of these exerts the greatest influence on the cardiovascular system when released into circulation in high amounts. Action on the heart and vasculature can cause potentially lethal arrhythmias, often in the setting of comorbid blood pressure derangements. In a review of electrocardiograms obtained on pheochromocytoma patients (n = 650) treated at our institution over the last decade, severe and refractory sinus tachycardia, atrial fibrillation, and ventricular tachycardia were found to be the most common or life-threatening catecholamine-induced tachyarrhythmias. These arrhythmias, arising from catecholamine excess rather than from a primary electrophysiologic substrate, require special considerations for treatment and complication avoidance. Understanding the synthesis and release of catecholamines, the adrenoceptors catecholamines bind to, and the cardiac and vascular response to epinephrine and norepinephrine underlies optimal management in catecholamine-induced tachyarrhythmias.
Topics: Adrenal Gland Neoplasms; Humans; Patient Care Management; Pheochromocytoma; Tachycardia
PubMed: 32703516
DOI: 10.1016/j.jacc.2020.04.080 -
Endocrine Pathology Jun 2021Abdominal paragangliomas and pheochromocytomas (PPGLs) are rare neuroendocrine tumors of the infradiaphragmatic paraganglia and adrenal medulla, respectively. Although... (Review)
Review
Abdominal paragangliomas and pheochromocytomas (PPGLs) are rare neuroendocrine tumors of the infradiaphragmatic paraganglia and adrenal medulla, respectively. Although few pathologists outside of endocrine tertiary centers will ever diagnose such a lesion, the tumors are well known through the medical community-possible due to a combination of the sheer rarity, their often-spectacular presentation due to excess catecholamine secretion as well as their unrivaled coupling to constitutional susceptibility gene mutations and hereditary syndromes. All PPGLs are thought to harbor malignant potential, and therefore pose several challenges to the practicing pathologist. Specifically, a responsible diagnostician should recognize both the capacity and limitations of histological, immunohistochemical, and molecular algorithms to pinpoint high risk for future metastatic disease. This focused review aims to provide the surgical pathologist with a condensed update regarding the current strategies available in order to deliver an accurate prognostication of these enigmatic lesions.
Topics: Adrenal Gland Neoplasms; Biomarkers, Tumor; Humans; Immunohistochemistry; Paraganglioma; Pathology, Molecular; Pheochromocytoma
PubMed: 33768452
DOI: 10.1007/s12022-021-09675-0 -
BMJ Case Reports Nov 2017A 56-year-old healthy woman presents with 2-year history of symptoms classic for pheochromocytoma. Evaluation revealed one of the largest cystic pheochromocytomas...
A 56-year-old healthy woman presents with 2-year history of symptoms classic for pheochromocytoma. Evaluation revealed one of the largest cystic pheochromocytomas reported but without any metastatic disease. After achieving medical management of her symptoms, surgical removal was performed successfully and without any complications intraoperatively. Pathology of the mass confirmed the diagnosis. The patient had complete resolution of her symptoms thereafter.
Topics: Adrenal Gland Neoplasms; Adrenalectomy; Female; Humans; Middle Aged; Pheochromocytoma; Rare Diseases; Tomography, X-Ray Computed; Treatment Outcome; Ultrasonography
PubMed: 29122903
DOI: 10.1136/bcr-2017-222264 -
Current Opinion in Endocrinology,... Jun 2022Many publications review perioperative management of pheochromocytomas/paragangliomas (PPGLs); however, a large population, including 10-20% of metastatic PPGL patients,... (Review)
Review
PURPOSE OF REVIEW
Many publications review perioperative management of pheochromocytomas/paragangliomas (PPGLs); however, a large population, including 10-20% of metastatic PPGL patients, have inoperable disease. This has necessitated the development of noninvasive treatments (e.g., radio/chemotherapy), which, in affording disease-modification, have led to an ever-growing population of surviving patients with inoperable PPGL. These patients experience debilitating symptoms arising from discomforts related to the masses themselves (e.g., pain from osseous metastasis) and symptoms from tumoral catecholamine production and release. Unfortunately, management of these conditions is not yet well-defined. Adding further insult-to-injury, these noninvasive treatments can trigger catecholamine release, worsening catecholamine-induced symptoms. Herein, we detail these ailments and their management, especially while patients receive these noninvasive treatments.
RECENT FINDINGS
Improved diagnostic evaluations have allowed for earlier detection of PPGL, prolonging survival in patients with inoperable PPGLs. Accordingly, noninvasive treatment strategies have rapidly evolved alongside state-of- the-art theranostics and genetic testing, which inform ongoing management and therapeutic response.
SUMMARY
While treatments afford improved survival, there must be a corresponding attention to quality-of-life. This is ensured by employing supportive management, which mitigates debilitating symptoms. This is best accomplished with a multidisciplinary approach and familiarity with genetic and biochemical determinants which guide patient education and management.
Topics: Adrenal Gland Neoplasms; Catecholamines; Genetic Testing; Humans; Paraganglioma; Pheochromocytoma
PubMed: 35621181
DOI: 10.1097/MED.0000000000000724 -
The Quarterly Journal of Nuclear... Dec 2008Pheochromocytomas are rare tumors arising from chromaffin cells of adrenal medullary or extra-adrenal paraganglionic tissue. These tumors are characterized by synthesis,... (Review)
Review
Pheochromocytomas are rare tumors arising from chromaffin cells of adrenal medullary or extra-adrenal paraganglionic tissue. These tumors are characterized by synthesis, storage, metabolism and secretion of catecholamines. Similar to the sympathetic nervous system, pheochromocytomas express cellular norepinephrine transporters (NET) through which catecholamines can enter pheochromocytoma cells to be stored in vesicles. Metaiodobenzylguanidine (MIBG) resemblance to norepinephrine and its good affinity and uptake by NET resulted in its use in pheochromocytoma diagnosis from 1981. Both [(123)I]MIBG and [(131)I]MIBG (lower sensitivity) scintigraphy are used for localization of these tumors. Recent discoveries of different hereditary syndromes associated with pheochromocytomas led to the identification of several and new distinct genotype-phenotype associations. Importantly, with this distinction of clinical phenotypes, MIBG was found to have a different performance in subsets of pheochromocytoma patients. Reduced sensitivity of MIBG scintigraphy in some familial paraganglioma syndromes, malignant disease and extra-adrenal paragangliomas has been found. Therefore, newer compounds, especially for positron emission tomography (PET), such as [(11)C]hydroxyephedrine ([(11)C]HED), [(18)F]fluoro-2-deoxy-D-glucose ([(18)F]FDG), [(18)F]fluoro-dihydroxyphenylalanine ([(18)F] FDOPA) and [(18)F]fluorodopamine ([(18)F]FDA) have emerged and were found to be superior to MIBG in the localization of certain types of pheochromocytoma and paragangliomas. Finally, using [(131)I]MIBG represents an important treatment option in patients with malignant pheochromocytoma, but the development of newer treatment modalities is expected. In this review, we provide the reader with an overview of the current standing of [(123)I]- and [(131)I]MIBG in diagnosis and treatment of pheochromocytoma amongst the newer PET imaging agents.
Topics: 3-Iodobenzylguanidine; Humans; Iodine Radioisotopes; Paraganglioma; Pheochromocytoma; Positron-Emission Tomography
PubMed: 19088695
DOI: No ID Found -
Cytogenetic and Genome Research 2016Pheochromocytomas (PCC) and sympathetic paragangliomas (PGL) are rare neuroendocrine tumors, which derive from chromaffin cells occurring in the adrenal medulla and... (Review)
Review
Pheochromocytomas (PCC) and sympathetic paragangliomas (PGL) are rare neuroendocrine tumors, which derive from chromaffin cells occurring in the adrenal medulla and extra-adrenal sympathetic paraganglia. PCC and PGL are often benign, catecholamine-producing tumors, responsible for a myriad of symptoms that may be potentially hazardous to the patient. In contrast, nonsecreting parasympathetic PGL, derived from chief cells, develop mainly in the head and neck region. Although PCC/PGL are more commonly sporadic tumors, germline mutations are present in up to 40% of the patients, ranking these tumors among those with the highest degree of heritability. PCC/PGL are associated with a variety of hereditary syndromes, comprising genetic alterations in RET, NF1, VHL, and SDHx genes, the last 2 being involved in regulating the hypoxia pathway. Additional hypoxia pathway-related genes have been recently associated with PCC/PGL development, namely EGLN1 and EPAS1. Thus, dysregulation of the hypoxia pathway seems to play a major role in PCC/PGL development, in particular through the stabilization of hypoxia-inducible factors and the appearance of a pseudohypoxia signature. This article is focused on reviewing the tumorigenic mechanisms resultant from VHL, SDHx, EGLN1, and EPAS1 mutations, as well as the associated tumors, namely PCC/PGL, and extra manifestations such as polycythemia. In the light of the recent discoveries, hypoxia pathway molecules appear as key players in PCC/PGL development.
Topics: Cell Hypoxia; Humans; Mutation; Neovascularization, Pathologic; Paraganglioma; Pheochromocytoma
PubMed: 28231563
DOI: 10.1159/000457479 -
Clinical Endocrinology Feb 2010Formerly used concepts for phaeochromocytomas and paragangliomas have been challenged by recent discoveries that at least 24% of tumours are familial and thereby often... (Review)
Review
Formerly used concepts for phaeochromocytomas and paragangliomas have been challenged by recent discoveries that at least 24% of tumours are familial and thereby often multiple in various locations throughout the body. Furthermore, tumours are often malignant and perhaps more aggressive if associated with SDHB gene mutations. Some paragangliomas are clinically silent and may present only with dopamine hypersecretion. In the current era where CT and MRI are more commonly used, tumours are more often found as incidentalomas and MRI may be less specific for phaeochromocytoma and paraganglioma than previously thought. Because of unique tumour characteristics (e.g. the presence of cell membrane and intracellular vesicular norepinephrine transporters) these tumours were 'born' to be imaged by means of specific functional imaging approaches. Moreover, additional recent discoveries related to apoptosis, hypoxia, acidosis, anaerobic glycolysis and angiogenesis, often disturbed in tumour cells, open new options and challenges to specifically image phaeochromocytomas and paragangliomas and possibly link those results to their pathophysiology, genotypic alterations and metastatic potential. Functional imaging, especially represented by positron emission tomography (PET), offers an excellent approach by which tumour-specific processes can be detected, evaluated and seen in the context of tumour-specific behaviour and its genetic signature. In this review, we address the recent developments in new functional imaging modalities for phaeochromocytoma and paraganglioma and provide the reader with suggested imaging approaches in various phaeochromocytomas and paragangliomas of sympathetic origin. Current imaging algorithms of head and neck parasympathetic paragangliomas are not discussed. Finally, this review outlines some future perspectives of functional imaging of these tumours.
Topics: Humans; Magnetic Resonance Imaging; Paraganglioma; Pheochromocytoma; Positron-Emission Tomography; Radiography
PubMed: 19508681
DOI: 10.1111/j.1365-2265.2009.03648.x -
Journal of Clinical Hypertension... Jun 2013Pheochromocytomas and paragangliomas are rare tumors with high morbidity rates caused by excessive catecholamine secretion, even though the majority of tumors are... (Review)
Review
Pheochromocytomas and paragangliomas are rare tumors with high morbidity rates caused by excessive catecholamine secretion, even though the majority of tumors are benign. The use of perioperative blockade regimens, together with improved surgical techniques, has greatly impacted the perioperative morbidity associated with these tumors. The old dogma of the "tumor of tens" no longer holds true. For example, at least one third of all pheochromocytomas and paragangliomas are hereditary, with mutations in 1 of 10 well-characterized susceptibility genes, and one quarter of all tumors are malignant. This review focuses on the perioperative management of pheochromocytoma and paragangliomas and the clinical implications of the associated genetic mutations.
Topics: Adrenal Gland Neoplasms; Humans; Hypertension; Mutation; Paraganglioma; Pheochromocytoma
PubMed: 23730992
DOI: 10.1111/jch.12084 -
Cancer Control : Journal of the Moffitt... Apr 2011Pheochromocytomas and paragangliomas are intra- and extra-adrenal neoplasms that are rarely malignant. The treatment of those that are malignant has remained a challenge... (Review)
Review
BACKGROUND
Pheochromocytomas and paragangliomas are intra- and extra-adrenal neoplasms that are rarely malignant. The treatment of those that are malignant has remained a challenge because little was known about the molecular pathways involved in its malignant transformation. Recently, however, the genetic and molecular changes involved in malignant pheochromocytoma have come to be understood.
METHODS
The authors review the recent literature about the changing treatment options for malignant pheochromocytomas and paragangliomas.
RESULTS
Traditional treatments for malignant pheochromocytoma remain unsuccessful. With the advances made in genomics and proteomics, novel pathways in pheochromocytoma carcinogenesis are becoming the targets of new treatment strategies and show promising results.
CONCLUSIONS
Although several studies and clinical trials show great promise for improving the treatment of pheochromocytomas and paragangliomas, the hope is that future collaborative efforts will allow for prospective clinical trials using an evidenced-based approach.
Topics: 3-Iodobenzylguanidine; Adrenal Gland Neoplasms; Catheter Ablation; Humans; Molecular Targeted Therapy; Pheochromocytoma
PubMed: 21451453
DOI: 10.1177/107327481101800205