Materiały źródłowe

• #1 Pheochromocytoma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK589700/

  Pheochromocytomas clinical manifestations stem from the overproduction of catecholaminesa group of hormones and neurotransmitters essential for maintaining homeostasis and regulating the body’s response to stress. […] The clinical manifestations of these tumors are primarily due to the excessive secretion of catecholamines. […] Pheochromocytomas release catecholamines in different patterns, classified as paroxysmal, continuous, or mixed. Norepinephrine is typically released continuously, leading to persistent hypertension, while epinephrine is released in a paroxysmal manner, which can cause tachyarrhythmias. […] Catecholamines are produced in chromaffin cells, beginning with the rate-limiting conversion of tyrosine to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase. […] Pheochromocytomas can arise sporadically or have a familial origin. Recent studies suggest that up to 35% of cases may be linked to germline mutations.

• #2 Pheochromocytoma – Wikipedia

  https://en.wikipedia.org/wiki/Pheochromocytoma

  Pheochromocytoma is a rare tumor of the adrenal medulla composed of chromaffin cells and is part of the paraganglioma (PGL) family of tumors, being defined as an intra-adrenal PGL. These neuroendocrine tumors can be sympathetic, where they release catecholamines into the bloodstream which cause the most common symptoms, including hypertension (high blood pressure), tachycardia (fast heart rate), sweating, and headaches. […] Current estimates predict that upwards of 40% of all pheochromocytomas are related to an inherited germline susceptibility mutation. Of the remaining 60% of tumors, more than 30% are associated with a somatic mutation. Given the high association with genetic inheritance, the United States Endocrine Society recommends that all patients diagnosed with a pheochromocytoma undergo an evaluation with a genetic counselor to consider genetic testing.

• #3 Pheochromocytomas in Animals – Endocrine System – Merck Veterinary Manual

  https://www.merckvetmanual.com/endocrine-system/neuroendocrine-tumors/pheochromocytomas-in-animals

  Pheochromocytomas arise from the adrenal medullary chromaffin cells that normally synthesize and secrete the catecholamines epinephrine and norepinephrine. […] Pheochromocytomas are rare tumors that affect the adrenal gland. […] Pheochromocytomas have been reported in multiple species, most commonly in dogs. […] Clinical signs in affected patients are nonspecific, and the diagnosis can be challenging.

• #4 Pheochromocytoma: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/124059-overview

  A pheochromocytoma is a rare, catecholamine-secreting tumor derived from chromaffin cells. […] The clinical manifestations of a pheochromocytoma result from excessive catecholamine secretion by the tumor. Secretion may occur either intermittently or continuously. Catecholamines typically secreted are norepinephrine and epinephrine; some tumors produce dopamine. […] Catecholamine secretion in pheochromocytomas is not regulated in the same manner as in healthy adrenal tissue. Unlike the healthy adrenal medulla, pheochromocytomas are not innervated, and catecholamine release is not precipitated by neural stimulation. The trigger for catecholamine release is unclear, but multiple mechanisms have been postulated, including direct pressure, medications, and changes in tumor blood flow. […] Relative catecholamine levels also differ in pheochromocytomas. Most pheochromocytomas secrete norepinephrine predominantly, whereas secretions from the normal adrenal medulla are roughly 85% epinephrine.

• #5 PHEOCHROMOCYTOMA – PATHOLOGY – Pathology Made Simple

  https://ilovepathology.com/pheochromocytoma-pathology/

  Pheochromocytomas are neoplasms of the adrenal medulla composed of chromaffin cells, which can release catecholamines and sometimes peptide hormones, primarily affecting the body’s hormonal balance. […] Pheochromoblasts give rise to chromaffin cells, which can form pheochromocytomas when located in the adrenal medulla or paragangliomas when these cells are extra-adrenal. […] Genetic mutations in genes such as RET, NF1, VHL, EPAS1, and the Succinate Dehydrogenase Complex (SDHB, SDHC, SDHD) can lead to uncontrollable cell growth and tumor development by affecting pathways like the Growth Factor Receptor Pathway and Hypoxia-Inducible Factors. […] Pheochromocytomas are often linked with several genetic conditions, such as Multiple Endocrine Neoplasia type 2A and 2B, Neurofibromatosis type 1, and hereditary paraganglioma syndromes.

• #6

  https://www.clinicsinsurgery.com/full-text/cis-v2-id1517.php

  The goals of preoperative management are to reduce the possibility of a catecholamine surge and its effect on target organs upon anesthesia induction and tumor manipulation while ensuring stability in postoperative care. […] Tyrosine, the amino acid from which they are derived, is actively transported into chromaffin cells then hydroxylated to 3,4-dihydroxyphenylalamine (L-dopa) by tryosine hydroxylase, the rate limiting enzyme in the production of catecholamines. Tyrosine hydroxylase is the target of the drug metyrosine. […] E and NE activate three families of receptors. Alpha-1 adrenergic receptors operate postsynaptically to signal cells to open calcium ion channels. Alpha-2 adrenergic receptors operate on the presynaptic membrane to negatively regulate catecholamine release as well as post-synaptically. Together the alpha-adrenergic mediated reactions lead to vasoconstriction, bronchoconstriction, cardiac contractility, hepatic glucose production, decreased insulin release, and more. Beta-adrenergic receptors stimulate cAMP release in the affected cells as opposed to a calcium ion channel mediated system. This leads to cardio acceleration, increased myocardial strength, glycogenolysis, lipolysis, and increased glucagon release.

• #7 Metabolism and secretion mechanism of catecholamine syndrome and related treatment strategies – Liu – Journal of Xiangya Medicine

  https://jxym.amegroups.org/article/view/6390/html

  Catecholamine syndrome, also known as pheochromocytoma, is a kind of tumor that originate from adrenal or extra-adrenal chromaffin tissue, secreting a large amount of catecholamines. Some typical gene mutations such as VHL, RET and NF1 play roles in the development of pheochromocytoma. […] The same as most tumors, the etiology of sporadic pheochromocytoma has not been fully explained, but the familial pheochromocytoma is related to heredity. The occurrence of pheochromocytoma is usually along with the mutations of PHD2, VHL, SDHx, IDH, HIF2A, MDH2 and FH which are involved in the hypoxic pathway as well as RET, NF1, KIF1B, MAX and TMEM127 which are involved in the activating kinase signaling pathways. […] The activities of enzymes in catecholamine synthesis steps including tyrosine hydroxylase, L-aromatic amino acid decarboxylase and dopamine -hydroxylase are found higher in pheochromocytoma than that in normal adrenal medulla, which may be the cause of excessive catecholamine production in pheochromocytoma.

• #8 Pheochromocytoma pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Pheochromocytoma_pathophysiology

  It is understood that pheochromocytoma is mediated by excessive secretion of catecholamines and subsequent stimulation of adrenergic receptors. It arises from the chromaffin cells of the adrenal medulla and sympathetic ganglia. The pathophysiology of pheochromocytoma does not depend on the histological subtype. Malignant and benign pheochromocytomas share the same biochemical and histological features. […] It is understood that pheochromocytoma is the is mediated by excessive secretion of catecholamines and subsequent stimulation of adrenergic receptors. […] The exact mechanism responsible for surge in catecholamine secretion remains unclear but it has been postulated that certain medications (such as opiates, metoclopramide or beta blockers) and changes in tumor blood flow and pressure could be responsible factors.

• #9 Pheochromocytoma: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/124059-overview

  A retrospective study by Abou Azar et al found a direct correlation between the size of a pheochromocytoma and its biologic activity, reporting that tumors with a diameter of 2.3 cm or more result in levels of metanephrine and catecholamine that are three times the upper limit of normal. […] In hereditary forms of pheochromocytoma, the secretory profiles vary according to the underlying syndrome. Eisenhofer et al found that pheochromocytomas associated with VHL typically produce norepinephrine only, while those associated with MEN 2 and NF1 typically produce both epinephrine and norepinephrine. Tumors in patients with germline mutations of succinate dehydrogenase subunit genes (SDHB and SDHD), which cause familial paraganglioma, principally produce dopamine.

• #10 Pheochromocytoma and paraganglioma pathogenesis: learning from genetic heterogeneity | Nature Reviews Cancer

  https://www.nature.com/articles/nrc3648

  Pheochromocytomas and paragangliomas carry the highest degree of heritability (around 40%) of all human tumours and thus represent relevant models for the identification of driver mutations in cancer. […] More than 12 genes, belonging to a wide range of functional classes are mutated in the germ line or, less frequently, in somatic pheochromocytomas and paragangliomas, but many tumours remain genetically undefined. […] Two main transcription signatures, associated with hypoxia-related signals (cluster 1) and increased kinase signalling (cluster 2), underlie the various driver mutations, revealing pathway interactions and enabling the discovery of novel predisposing genes. […] Mutations of metabolism genes uncovered the cell growth-promoting effects of metabolism intermediates (succinate) through epigenetic (histone and DNA methylation) modulation and activation of a hypoxic response. […] Mechanisms involved in the malignant transformation of pheochromocytomas and paragangliomas are not fully elucidated, and treatment options for these tumours are still limited.

• #11 Pheochromocytoma and paraganglioma in genetic disorders – UpToDate

  https://www.uptodate.com/contents/pheochromocytoma-in-genetic-disorders

  Pheochromocytoma is a rare neoplasm, probably occurring in less than 0.2 percent of patients with hypertension. Pheochromocytoma in genetic disorders will be reviewed here. Most catecholamine-secreting tumors are sporadic. However, approximately 40 percent of patients have the disease as part of a familial disorder. Hereditary catecholamine-secreting tumors typically present at a younger age than sporadic neoplasms. Sporadic pheochromocytoma is usually diagnosed on the basis of symptoms or an incidental discovery on computed imaging, whereas syndromic pheochromocytoma is frequently diagnosed earlier in the course of disease because of biochemical surveillance or genetic testing. Familial pheochromocytoma is also diagnosed at a younger age because of much earlier symptomatic tumor development. Familial pheochromocytoma — There are several familial syndromic disorders associated with adrenal pheochromocytoma, all of which have autosomal dominant inheritance: von Hippel-Lindau (VHL) syndrome, multiple endocrine neoplasia type 2 (MEN2) and, less commonly, neurofibromatosis type 1 (NF1). The approximate frequency of pheochromocytoma in these disorders is 10 to 20 percent in VHL syndrome, 50 percent in MEN2, and 3 percent with NF1. […] Pheochromocytoma in genetic disorders will be reviewed here. The diagnosis and treatment of pheochromocytoma are discussed separately. […] Most catecholamine-secreting tumors are sporadic. However, approximately 40 percent of patients have the disease as part of a familial disorder.

• #12 Pheochromocytoma and Paraganglioma – Adrenal Gland Diseases – Endocrinology – Diseases – McMaster Textbook of Internal Medicine

  https://empendium.com/mcmtextbook/chapter/B31.II.11.11.

  Pheochromocytoma (PCC) and paraganglioma (PGL) are catecholamine-secreting tumors that arise from chromaffin cells of the adrenal medulla and extra-adrenal sympathetic ganglia, respectively. They account for 0.5% of all causes of hypertension. The majority of these rare tumors occur sporadically. Approximately 40% occur as part of a familial syndrome, 10% are bilateral, 10% are extra-adrenal, 10% are found in children, 10% are recurrent, and 10% are malignant. […] Hereditary PCC/PGL syndromes include multiple endocrine neoplasia types 2 and 3 (MEN 2/MEN 2a MEN 3/MEN 2b), von Hippel-Lindau disease (VHL) (cerebroretinal angiomatosis), neurofibromatosis type 1 (NF1), Carney triad (gastrointestinal stromal tumor, pulmonary chondromas, and functional extra-adrenal paragangliomas), and mutations in the succinate dehydrogenase (SDH), TMEM127, and MAX genes.

• #13 Clinical Syndromes and Genetic Screening Strategies of Pheochromocytoma and Paraganglioma

  https://www.jkcvhl.com/~jkcvhlco/index.php/jkcvhl/article/download/113/226/1378

  Pheochromocytomas (PCCs) are rare neuroendocrine tumors that originate from chromaffin cells of the adrenal medulla, and paragangliomas (PGLs) are extra-adrenal pheochromocytomas. […] PCC and PGL are thought to have the highest heritability among human tumors. […] Up to 40% of PCC and PGL are attributed to germline mutations, and overall, germline and somatic mutations can be present in 60% of PCC and PGL. […] The VHL gene encodes the VHL protein (pVHL), which has a wide range of functions, the most important being the degradation of hypoxia inducible factors (HIFs). […] Without degradation, HIFs can be translocated to the nucleus and initiate transcription of multiple target genes, which can promote cell proliferation, angiogenesis, erythropoiesis, and anaerobe metabolism. […] Mutations in the succinate dehydrogenase (SDH, mitochondrial complex II) and its subunit genes (SDHA, SDHB, SDHC, SDHD, and SDHAF2) can lead to FPGLs.

• #14 Genetics and molecular pathogenesis of pheochromocytoma and paraganglioma – PubMed

  https://pubmed.ncbi.nlm.nih.gov/23061808/

  Although most pheochromocytomas (PCCs) and paragangliomas (PGLs) are sporadic, molecular genetic medicine has revealed that a considerable number of patients with apparently sporadic PCC actually have a genetic predisposition to the development of these tumors. […] After decades of intensive research, several genes are now known to play an important role in the pathogenesis of PCC. At present, these are RET proto-oncogene, von Hippel-Lindau disease tumor suppressor gene (VHL), neurofibromatosis type 1 tumor suppressor gene (NF1), genes encoding the succinate dehydrogenase (SDH) complex subunits SDHB, SDHC, and SDHD, but also SDHA, the gene encoding the enzyme responsible for the flavination of SDHA (SDHAF2 or hSDH5), and the newly described TMEM127 and MAX tumor suppressor genes. […] Studying the pathogenesis and the molecular correlation of these mutations has revealed the existence of two main transcription signatures: a pseudohypoxic cluster (VHL and SDH mutations) and a cluster rich in kinase receptor signaling and their downstream pathways (RET, NF1, TMEM127, and MAX mutations).

• #15 Advances in the management of pheochromocytoma – a short review | Miciak | Nowotwory. Journal of Oncology

  https://journals.viamedica.pl/nowotwory_journal_of_oncology/article/view/96815

  Pheochromocytoma is a rare neuroendocrine neoplasm. It is characterized by overproduction of catecholamines, which causes clinical symptoms associated with elevated blood pressure values, and can even lead to life-threatening complications. […] The tumor can be associated with genetic syndromes such as multiple endocrine neoplasia type 2 (MEN-2) or von HippelLindau syndrome (VHL), and currently available and constantly evolving genetic testing makes it possible to detect the inherited form and plan appropriate therapy. […] Currently, about 30-40% of all pheochromocytoma cases are considered to be hereditary. […] The pathogenesis of pheochromocytoma also involves the genes ATRX and H3F3A. These genes are responsible for chromatin remodeling and H3.3 histone but are not classified into the aforementioned clusters.

• #16 Pheochromocytoma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK589700/

  Genetic testing should be considered for all patients diagnosed with pheochromocytoma. […] Several genes associated with the development of pheochromocytomas have been identified and categorized into 3 clusters based on the mechanism of tumorigenesis: Pseudohypoxia pathway (cluster 1), Kinase-signaling pathway (cluster 2), Somatic cluster (cluster 3). […] The definitive treatment for pheochromocytoma is surgical resection, with preoperative – and -adrenergic blockade being crucial. […] The key elements of perioperative management are 4-fold. First, prevention of catecholamine surge is achieved through minimal handling of the lesion and avoiding spillage of tumor contents, particularly in cystic lesions.

• #17 Advances in the management of pheochromocytoma – a short review | Miciak | Biuletyn Polskiego Towarzystwa Onkologicznego Nowotwory

  https://journals.viamedica.pl/biuletyn_pto/article/view/99872/77097

  The pathogenesis of pheochromocytoma can be divided into three clusters, depending on their mechanism of action: pseudohypoxia, kinase signaling and Wnt signaling. […] Genetic testing can be used after a diagnosis of pheochromocytoma to exclude an inherited form or to predict the prognosis and hormonal activity of the tumor. […] The principal treatment of a pheochromocytoma secreting significant amounts of hormones is surgical resection with perioperative adrenergic receptor blockade, as it is necessary to improve the patients condition as quickly as possible and prevent severe cardiovascular complications. […] The choice of the therapy should include factors such as the resectability of the tumor, its infiltration of adjacent structures, the presence of distant metastases, the amount of hormones secreted by the tumor, its growth rate and the patients comorbidities. […] The large range of chemotherapeutics in clinical trials offers hope for the future in pheochromocytoma therapy.

• #18 Frontiers | Editorial: Recent Advances in Pheochromocytoma and Paraganglioma: Molecular Pathogenesis, Clinical Impacts, and Therapeutic Perspective

  https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2021.720983/full

  In this Research Topic, we have collected recent developments in research into Pheochromocytomas and Paragangliomas (PPGLs), highlighting their molecular mechanisms, clinical manifestations, and improved therapeutic management. […] Recent advances in understanding of the molecular biology of PPGLs, however, offer potential to open pathways to improve therapeutic interventions for PPGL tumors. […] Pseudohypoxia plays important roles in the tumourigenesis of PPGLs. Mutations in Von Hippel-Lindau (VHL) and hypoxia-induced factor (HIF) related genes, including PHD, VHL, HIF-2A (EPAS1), and SDHx, which are known as VHL/HIF axis genes, are common in PPGLs. […] Also, VHL/HIF-mediated pseudohypoxia has a critical role in the pathogenesis of PPGLs. […] Succinate plays critical roles in PPGL pathogenesis and the accumulation of succinate receptor 1 (SUCNR1) in SDHx mutated PPGLs has been previously reported.

• #19 Genetics of Pheochromocytomas and Paragangliomas Determine the Therapeutical Approach

  https://www.mdpi.com/1422-0067/23/3/1450

  Pheochromocytomas and paragangliomas are the most heritable endocrine tumors. […] All these genetic alterations are clustered in distinct groups which determine the pathomechanisms. […] Although the tissue origin of these tumors is identical, the differences in tumorigenesis are remarkably distinct. Different molecular clusters are distinguished based on the pathogenesis. […] The elevated level of succinate or fumarate activates the pseudohypoxic pathway by inhibiting Hypoxia-Inducible Factor- (HIF) prolyl hydroxylases (and therefore stabilizing HIF under normoxic conditions) and promotes the hypermethylation of histone and DNA as competitive inhibitors of alpha-ketoglutarate-dependent dioxygenases. […] A common feature of gene mutations associated with the pseudohypoxic pathway is that they induce a hypoxic response under normoxic conditions during constitutive activation of the HIF pathway.

• #20 15 YEARS OF PARAGANGLIOMA: Genetics and mechanism of pheochromocytoma–paraganglioma syndromes characterized by germline SDHB and SDHD mutations in: Endocrine-Related Cancer Volume 22 Issue 4 (2015)

  https://erc.bioscientifica.com/view/journals/erc/22/4/T71.xml

  Pathogenesis of PPGLs caused by SDH mutations remains poorly understood. SDH catalyzes the oxidation of succinate to fumarate in the Krebs cycle and functions as mitochondrial complex II by transferring the extracted electrons to ubiquinone in the electron transport chain. Loss of SDH activity leads to increased succinate and reactive oxygen species (ROS). Thus, succinate and ROS are considered as the signaling molecules that ultimately trigger tumor formation upon SDH mutations. Since discovery of the first mutations in familial PPGLs in 2000-2001, alternative models for tumor development have been advanced using different observations and experimental models that studied the consequences of SDH genetic loss. These models can be broadly classified as constitutive hypoxic drive, inhibition of developmental neuronal culling and histone/genome hypermethylation.

• #21 15 YEARS OF PARAGANGLIOMA: Genetics and mechanism of pheochromocytoma–paraganglioma syndromes characterized by germline SDHB and SDHD mutations in: Endocrine-Related Cancer Volume 22 Issue 4 (2015)

  https://erc.bioscientifica.com/view/journals/erc/22/4/T71.xml

  The most common phenotypic manifestation of germline SDH mutations is the development of PPGL tumors. Gastrointestinal stromal tumors and renal carcinoma also develop in a small minority of subjects who carry germ line SDH mutations. HNPGL, especially the carotid body (CB) paraganglioma, are characteristically associated with germ line mutations in structural subunit genes SDHD, SDHC, SDHB, and in regulatory subunit genes SDHAF2. […] Recent genome-wide expression profiling studies show strong induction of hypoxia and angiogenesis pathways in SDH- and VHL-related PPGL. SDH and VHL mutations induce both protein encoding mRNAs and miRNAs (miR-210) that are implicated in cellular adaptation to hypoxia. Although certain differences in the induced genes were observed, the broad overlap amongst the hypoxia induced genes between SDH- and VHL-related paragangliomas strongly suggest that pathogenesis of SDH tumors involves constitutive hypoxic stimulation.

• #22 Molecular markers of paragangliomas/pheochromocytomas | Oncotarget

  https://www.oncotarget.com/article/15201/text/

  An important feature of these tumors is their high heritability rate as compared with other neoplasias. Almost 40% of paragangliomas exhibit germline mutations in at least one out of more than 30 potentially causative genes. Approximately 25-30% of these tumors develop under conditions of a hereditary tumor syndrome a third of which are caused by mutations in the Von Hippel Lindau (VHL) gene. Additionally, 25-30% of the tumors carry somatic mutations in the RET, VHL, neurofibromin 1 (NF1), and MYC-associated factor X (MAX) genes among others. […] This review represents the most complete compilation of information available to date regarding the mechanisms of paraganglioma/pheochromocytoma development and the associated mutations. These data will improve the understanding of the pathogenesis of these tumors and likely reveal certain features that may be useful toward facilitating early tumor diagnosis, predicting their malignancy, and determining new targets for therapy.

• #23 Pheochromocytoma | 5-Minute Clinical Consult

  https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/116451/all/Pheochromocytoma

  Pheochromocytoma is an endocrine tumor of chromaffin cells of adrenal medulla. […] Pheochromocytomas produce catecholamines in circulation that causes episodic hypertension. Classic triad of symptoms include: Severe headache, sweating, and palpitations. […] Genetics Pheochromocytomas are mostly sporadic but can also be familial. Most commonly, familial cases of pheochromocytoma are caused by mutation in succinate dehydrogenase (SDH) subunit gene. Familial pheochromocytomas are all autosomal dominant inheritance. Genes involved in pathogenesis includes: NF1 tumor suppressor gene (NH-1), RET proto-oncogene mutation, VHL gene mutation, TMEM127 tumor suppressor gene mutation, SDH subunit gene mutations (SDHB, SDHC, SDHD, SDHAF2, SDHA).

• #24 Pathophysiology and Management of Glycemic Alterations before and after Surgery for Pheochromocytoma and Paraganglioma

  https://www.mdpi.com/1422-0067/24/6/5153

  Glycemic alterations are frequent in patients with pheochromocytoma and paraganglioma (PPGL), but the real incidence of secondary diabetes mellitus (DM) is uncertain, because prospective multicenter studies on this topic are lacking in the literature. The main pathophysiological mechanisms of glucose homeostasis alterations in PPGL, related to catecholamine hypersecretion, are impaired insulin and glucagon-like peptide type 1 (GLP-1) secretion and increased insulin resistance. […] The most important mechanisms regarding glucose homeostasis alterations in PPGLs are impaired insulin secretion and/or increased insulin resistance, but it is still unclear which of these factors is the most prevalent one. Several studies demonstrated that insulin secretion is compromised in PPGL as the result of the inhibitory effect of catecholamines, mainly through adrenergic α2 receptors of β-cells in pancreatic islets. Among the different α2 receptors subtypes, the α2A ones suppress insulin secretion in pancreatic β-cells. On the other side, increased insulin resistance is related to multiple mechanisms.

• #25 Pathophysiology and Management of Glycemic Alterations before and after Surgery for Pheochromocytoma and Paraganglioma

  https://www.mdpi.com/1422-0067/24/6/5153

  Although PPGLs are well known to be associated with glucose intolerance, there are limited studies available that explore the effect on insulin secretion and sensitivity. In a retrospective study on 13 patients with PPGLs, Komada et al. documented that chromaffin tumors could impair the insulin secretory response, especially in the first phase of secretion. […] Furthermore, some data suggested a possible relationship between PPGL-related impaired glucose metabolism and adiponectin, an adipocytokine with an anti-diabetic, anti-inflammatory and anti-atherogenic action. […] According to the different affinities of epinephrine and norepinephrine on adrenergic receptors and their different effects on glucose metabolism, it is likely that the tumor secretory phenotype could differently affect glucose metabolism in PPGL patients.

• #26 Frontiers | Recent Advances in Pheochromocytoma and Paraganglioma: Molecular Pathogenesis, Clinical Impacts, and Therapeutic Perspective, volume II

  https://www.frontiersin.org/research-topics/55553/recent-advances-in-pheochromocytoma-and-paraganglioma-molecular-pathogenesis-clinical-impacts-and-therapeutic-perspective—volume-iiundefined

  Pheochromocytoma and paraganglioma are the primary types of neuroendocrine tumors, although they are relatively rare compared to other tumors, originating from chromaffin tissue in the adrenal medulla and/or autonomic nervous system ganglia. […] These tumors produce excessive catecholamines, the effects of which are manifested through various cardiac-related symptoms, such as hypertension due to increased total peripheral resistance, heart attacks despite no prior history, non-cardiogenic pulmonary shock, oedema, arrhythmias, and sudden death. […] The benign pheochromocytoma and paraganglioma can progress into highly malignant phenotypes many years after the initial diagnosis, though the exact mechanisms of this are poorly understood. […] Thus the genetic factors causing them are highly diverse, making them extremely heterogenic.

• #27 SciELO Brazil – Pheochromocytoma: current perspectives in the pathogenesis, diagnosis, and management Pheochromocytoma: current perspectives in the pathogenesis, diagnosis, and management

  https://www.scielo.br/j/abem/a/k7ySnqSLwNrGC7xqcPR694P/?lang=en&format=html

  Pheochromocytoma: current perspectives in the pathogenesis, diagnosis, and management […] The hypertension in pheochromocytoma is a complex process influenced by the sympathetic nervous system (SNS) and circulating catecholamines, and by alterations in cardiovascular response to catecholamines. Patients with pheochromocytoma can be normotensive or only moderately hypertensive despite high circulating levels of catecholamines. Several hypotheses have been proposed to explain the altered response of vascular smooth muscle. These include hypovolemia, increased production of vasodilator agents (such as dopa or prostaglandins), and down-regulation of alpha-1 adrenergic receptors. […] […] Despite the presence of several factors that tend to alter vascular smooth muscle responsiveness to circulating catecholamines, sudden and significant rises in arterial pressure are common in patients with pheochromocytoma. These episodes occur even when there are no significant changes in the circulating levels of catecholamines. This may be attributable, in part, to the fact that in pheochromocytoma, the SNS is intact and remains active. […]

• #28 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Causes-and-Symptoms-of-Pheochromocytoma.aspx

  Pheochromocytomas are neural crest-derived tumors that produce catecholamines, such as epinephrine and norepinephrine, and arise mainly from the adrenal gland. […] All these functional chromaffin tumors can result in substantial morbidity and mortality due to catecholamine over-secretion. […] The catecholamines epinephrine and norepinephrine exert their action on – and -adrenoceptors that are found throughout the human body with various organ-specific distributions. […] Both catecholamines show overlapping but also distinctive activity on the different groups of those adrenoreceptors. […] Specifically, epinephrine has stronger activity on 2-adrenoceptors than norepinephrine, whereas norepinephrine is considered a more potent agonist of 1-adrenoceptors. […] Still, the propinquity of sites of epinephrine and norepinephrine release to aforementioned adrenoceptors and the ensuing concentrations at the effector sites are two key determinants of adrenoceptor-mediated clinical responses to these two aromatic amines (i.e. catecholamines).

• #29 PHEOCHROMOCYTOMA – PATHOLOGY – Pathology Made Simple

  https://ilovepathology.com/pheochromocytoma-pathology/

  There can be significant amount of nuclear pleomorphism in pheochromocytoma. However, to render a diagnosis of Malignancy, once should demonstrate evidence of metastasis either to regional lymph nodes or distant organs. […] Catecholamine cardiomyopathy is a result of the excessive secretion of catecholamines (epinephrine and norepinephrine) by pheochromocytomas, leading to direct toxicity on the myocardium or through constriction of myocardial blood vessels, ischemic damage, focal necrosis, mononuclear infiltrates, and interstitial fibrosis. […] Diagnosis involves demonstrating increased urinary excretion of free catecholamines, vanillylmandelic acid, and metanephrines. […] Treatment typically involves surgical excision of isolated benign tumors, with preoperative and intraoperative management using adrenergic-blocking agents to prevent hypertensive crises.

• #30 Pheochromocytoma – Wikipedia

  https://en.wikipedia.org/wiki/Pheochromocytoma

  Determining the genetic status of a pheochromocytoma patient is crucial each gene is inherited in a different pattern, associated with specific disease characteristics, and may respond more favorably to certain treatment options. Furthermore, early identification can guide physicians on screening recommendations for first degree relatives of patients with pheochromocytoma. […] Current research hypothesizes that the tumor secretes massive amounts of catecholamines, which directly interact with myocardial (heart) tissue and exert negative effects including oxygen deprivation, leading to accelerated scarring and cell death.

• #31 Clinical Syndromes and Genetic Screening Strategies of Pheochromocytoma and Paraganglioma

  https://www.jkcvhl.com/~jkcvhlco/index.php/jkcvhl/article/download/113/226/1378

  It is worth noting that mutation in SDHB is possibly related to malignancy and poor prognosis. […] Genetic screening is useful to identify carriers of the pathogenic mutations of PCC and PGL. […] As PCC/PGL accounts for the highest proportion of hereditary-related tumors, it is recommended that all patients with PCC/PGL should be tested for genetic mutations for the following reasons: (i) up to 40% patients carry disease-causing germline mutations; (ii) even for sporadic patients, the overall frequency of germline mutation is higher than 10%; (iii) specific genetic mutations are related to malignant PCC/PGL. […] In the diagnosis of PCC/PGL, three types of targeted NGS gene panels have been recommended. […] Although PCC and PGL are both neuroendocrine tumors arising from chromaffin cells and regarded as the same disease, their location and hereditary background are different.

• #32 Genetics of Pheochromocytomas and Paragangliomas Determine the Therapeutical Approach

  https://www.mdpi.com/1422-0067/23/3/1450

  The most common metastatic sites are lymph nodes, bone, liver and lungs. […] The risk factors for metastatic disease additionally to germline SDHB-mutation comprise of noradrenergic or dopaminergic phenotype, size (>5 cm), and extra-adrenal location. […] This brief review intends to give an insight into the specific molecular pathomechanism of the PPGL clusters and highlights the differences between them regarding clinical outcome and patient management. […] The clinical relevance of genetic background of PPGL tumors is also summarized to draw the attention to the existing genotype–phenotype correlations and their implication in clinical use.

• #33 Advances in the management of pheochromocytoma – a short review | Miciak | Nowotwory. Journal of Oncology

  https://journals.viamedica.pl/nowotwory_journal_of_oncology/article/view/96815

  The presence of disseminated inoperable malignancy disqualifies from surgical treatment. […] Over the years, pheochromocytoma therapy has been based on several essential principles: surgery, chemotherapy and radiotherapy. Recently, due to the rapid development of molecular biology, we can also include individualized immune agents in the treatment. […] The large range of chemotherapeutics in clinical trials offers hope for the future in pheochromocytoma therapy.

• #34 Advances in the management of pheochromocytoma – a short review | Miciak | Nowotwory. Journal of Oncology

  https://journals.viamedica.pl/nowotwory_journal_of_oncology/article/view/96815

  Genetic testing can be used after a diagnosis of pheochromocytoma to exclude an inherited form or to predict the prognosis and hormonal activity of the tumor. […] The aim of this paper is to review the methods of diagnosis and therapy of pheochromocytoma and the progress that has been made over the past decade of research. […] The principal treatment of a pheochromocytoma secreting significant amounts of hormones is surgical resection with perioperative adrenergic receptor blockade, as it is necessary to improve the patients condition as quickly as possible and prevent severe cardiovascular complications. […] The choice of the therapy should include factors such as the resectability of the tumor, its infiltration of adjacent structures, the presence of distant metastases, the amount of hormones secreted by the tumor, its growth rate and the patients comorbidities.

• #35 Metabolism and secretion mechanism of catecholamine syndrome and related treatment strategies – Liu – Journal of Xiangya Medicine

  https://jxym.amegroups.org/article/view/6390/html

  Metyrosine specifically inhibits tyrosine hydroxylase which catalyzes the conversion from tyrosine to DOPA, the first and rate-limiting step in the pathway of catecholamine synthesis. Clinical trials have proved that metyrosine can inhibit the synthesis of catecholamines thus improves the symptoms caused by catecholamine excess such as hypertension.

• #36

  https://www.clinicsinsurgery.com/full-text/cis-v2-id1517.php

  Metyrosine, a tyrosine hydroxylase inhibitor, has also been used as a preoperative therapy for pheochromocytomas. A 1997 study showed that metyrosine in combination with phenoxybenzamine or prazosin greatly decreased the use of intraoperative vasopressors and phentolamine over just the alpha blockade alone. A 2015 study from a center that primarily used phenoxybenzamine in combination with metyrosine for preoperative management showed that when phenoxybenzamine was used without metyrosine cardiovascular specific complications (such as arrythmias) increased 16% and intraoperative hemodynamic variability (heart rate and systolic blood pressure) was significantly greater. However, metyrosine caused a number of side effects such as somnolence, depression and galactorrhea. Due to the potential side effects and few studies supporting its use, metyrosine is reserved for patients cannot tolerate alpha blockers or whose hypertension is refractory to alpha-receptor and calcium channel blockade. […] The totality of evidence in the literature suggests that calcium channel blockers are effective at managing intraoperative hemodynamic fluctuations, particularly in smaller tumors.

• #37 Gene Variants in Pheochromocytoma and Paraganglioma – EGA European Genome-Phenome Archive

  https://www.ega-archive.org/studies/phs002405

  Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors that arise from chromaffin cells in the adrenal medulla and in extra-adrenal locations, respectively. […] To date, over 20 susceptibility genes have been suggested to play a role in PPGL pathogenesis, with more genes still being researched. […] Knowledge of the genetic background and the genes involved in the pathogenesis of PPGL allows for clustering and/or development of targeted therapies for the tumors that cannot be surgically resected or tumors that have metastasized.

• #38 Malignant pheochromocytoma–paraganglioma: pathogenesis, TNM staging, and current clinical trials – SEARCH

  https://primo.qatar-weill.cornell.edu/discovery/fulldisplay/cdi_proquest_miscellaneous_1872575365/974WCMCIQ_INST:VU1

  Purpose of reviewPheochromocytomas and paragangliomas (PPGs) are rare neuroendocrine tumors. Over the last 15 years, substantial progress has been made toward understanding the clinical aspects and molecular origins of this disease. Nevertheless, predicting and managing malignancy remains the biggest challenge in clinical practice. The natural history of patients with malignant PPGs has not yet been described, and their prognosis varies. Currently, the diagnosis of malignant PPGs relies on the presence of metastases, by which time the disease is usually advanced. Better understanding of the clinical and molecular characteristics of patients with malignant PPGs has spurred several prospective clinical trials. […] Recent findingsSeveral molecular targeted therapies, a novel radiopharmaceutical medication that targets the catecholamine transporter, and immunotherapy are under evaluation for the treatment of patients with malignant PPGs. Furthermore, the identification of clinical predictors of malignancy and survival has led to the first TNM staging classification for PPGs. […] SummaryProspective clinical trials are providing patients with therapeutic options beyond systemic chemotherapy. The knowledge derived from these trials and from the evaluation of the TNM staging in clinical practice will help to clarify how to most effectively treat malignant PPGs.

• #39 Frontiers | Editorial: Recent Advances in Pheochromocytoma and Paraganglioma: Molecular Pathogenesis, Clinical Impacts, and Therapeutic Perspective

  https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2021.720983/full

  In this Research Topic, Matlac et al. reported the oncometabolic function of succinate in SDHx mutation driven PPGLs via SUCNR1 stimulation of the ERK pathway, and the capacity of SUCNR1 inhibitors to abrogate this effect. […] In conclusion, the information presented in this Research Topic provides an underlying molecular and genetic spectrum of PPGLs, unveiling their clinical implications, thereby enriching our understanding of the pathogenesis of the disease, which could improve clinical outcomes in patients with PPGLs.

• #40 Pheochromocytoma and High Blood Pressure

  https://www.verywellhealth.com/pheochromocytoma-and-high-blood-pressure-1763816

  Pheochromocytomas produce high levels of chemicals called catecholamines, which are strong hormones associated with stress, and they act on the cardiovascular system to increase heart rate, blood pressure, and blood flow. […] These tumors commonly produce epinephrine (adrenaline), norepinephrine and dopamine — three compounds that are among the strongest known for increasing blood pressure. […] Because pheochromocytomas produce large amounts of each of these hormones, the effects on blood pressure are typically very dramatic. […] Almost all patients with pheochromocytomas have elevated blood pressure, and the hallmark of high blood pressure caused by this condition is extreme blood pressure swings during the day. […] All pheochromocytomas need to be surgically removed. […] This is one of the rare cases where some attempt is made to reduce blood pressure before the surgery is done. […] The reasons for this are complicated but relate to the fact that this is high-risk and potentially dangerous surgery.

• #41

  https://www.clinicsinsurgery.com/full-text/cis-v2-id1517.php

  Pheochromocytomas and paragangliomas are catecholamine-producing neoplasms that can cause life-threatening hemodynamic instability, particularly intraoperatively, when the tumor is manipulated. Preoperative medical management reduces both preoperative morbidity and mortality. The current review discusses the latest literature on preoperative management. Preoperative strategies include a nonselective alpha-antagonist, selective alpha antagonists, calcium channel blockers, tyrosine hydroxylase inhibitors, and fluid and salt loading. Compared to selective alpha-antagonists, preparation with phenoxybenzamine prior to surgery is associated with superior intraoperative hemodynamic stability, but also more post-operative hypotension, adverse drug effects, and longer treatment period. No studies indicate a difference in clinical outcomes between phenoxybenzamine and selective alpha-antagonists. Calcium channel inhibitors have been shown in multiple studies to have similar hemodynamic stability and outcomes as patients with pre-operative alpha blockades, particularly in patients with smaller tumors. Metyrosine has been shown to attenuate intraoperative hemodynamic stability when used in conjugation with phenoxybenzamine or a selective alpha-antagonist. Magnesium-sulfate does not improve intraoperative hemodynamic instability when used in conjunction with nicardipine. Therefore multiple effective strategies exist to prevent morbidity and mortality associated with resection, however, a lack of preparation is not one of them.

• #42 Metabolism and secretion mechanism of catecholamine syndrome and related treatment strategies – Liu – Journal of Xiangya Medicine

  https://jxym.amegroups.org/article/view/6390/html

  Whats more, in pheochromocytoma patients, more than 94% of elevated plasma metanephrines concentrations are caused by metabolism of catecholamines through COMT. The metabolism happens in pheochromocytoma tumor cells, rather than in the blood circulation by the extra-adrenal COMT. […] The secretion of catecholamine and the accompanying hypertension are affected by many factors such as the triggers, tumor location, genetic background and so on. […] Pheochromocytoma has been proven to exhibit highly evident gene expression profiles in MEN2 and VHL syndrome which usually caused by the mutation of RET and VHL respectively. […] The mechanism of magnesium sulfate to lower blood pressure is mainly: (I) relaxation of vascular smooth muscle and expansion of vascular wall, (II) inhibition of adrenal medulla and adrenergic nerve endings to secrete catecholamine, and (III) direct inhibition of catecholamine receptors.

• #43 Genetics and molecular pathogenesis of pheochromocytoma and paraganglioma – PubMed

  https://pubmed.ncbi.nlm.nih.gov/23061808/

  However, the general mechanism in the pathogenesis of a syndrome does not entirely apply in the particular pathogenesis of PCC as a manifestation of that syndrome. A better understanding of the complexity and high genetic diversity of PCC and PGL may lead to more efficient diagnosis and management of the disease.

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