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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 -
Folia Morphologica 1988
Topics: Animals; Cats; Chromaffin System; Dogs; Guinea Pigs; Mast Cells; Paraganglia, Chromaffin; Rats; Rats, Inbred Strains
PubMed: 3410390
DOI: No ID Found -
Frontiers in Endocrinology 2018Pheochromocytomas and paragangliomas (PCCs/PGLs) are rare commonly benign neuroendocrine tumors that share pathology features and clinical behavior in many cases. While... (Review)
Review
Pheochromocytomas and paragangliomas (PCCs/PGLs) are rare commonly benign neuroendocrine tumors that share pathology features and clinical behavior in many cases. While PCCs are chromaffin-derived tumors that arise within the adrenal medulla, PGLs are neural-crest-derived tumors that originate at the extraadrenal paraganglia. Pheochromocytoma-paraganglioma (PPGL) syndromes are rapidly evolving entities in endocrinology and oncology. Discoveries over the last decade have significantly improved our understanding of the disease. These include the finding of new hereditary forms of PPGL and their associated susceptibility genes. Additionally, the availability of new functional imaging tools and advances in targeted radionuclide therapy have improved diagnostic accuracy and provided us with new therapeutic options. In this review article, we present the most recent advances in this field and provide an update of the biochemical classification that further reflects our understanding of the disease.
PubMed: 30538672
DOI: 10.3389/fendo.2018.00515 -
Cellular and Molecular Life Sciences :... Mar 2018Neuroblastoma (NB) is a tumor of the sympathoadrenal system arising in children under 15 years of age. In Germany, NB accounts for 7% of childhood cancer cases, but 11%... (Review)
Review
Neuroblastoma (NB) is a tumor of the sympathoadrenal system arising in children under 15 years of age. In Germany, NB accounts for 7% of childhood cancer cases, but 11% of cancer deaths. It originates from highly migratory progenitor cells that leave the dorsal neural tube and contribute neurons and glial cells to sympathetic ganglia, and chromaffin and supportive cells to the adrenal medulla and paraganglia. Clinically, histologically and molecularly, NBs present as extremely heterogeneous, ranging from very good to very poor prognosis. The etiology of NB still remains unclear and needs to be elucidated, however, aberrant auto- and paracrine embryonic cell communications seem to be likely candidates to initiate or facilitate the emergence, progression and regression of NB. The wingless-type MMTV integration site (WNT) family of proteins represents an evolutionary highly conserved signaling system that orchestrates embryogenesis. At least 19 ligands in the human, numerous receptors and co-receptors are known, which control not only proliferation, but also cell polarity, migration and differentiation. Here we seek to interconnect aspects of WNT signaling with sympathoadrenal and paraganglionic development to define new WNT signaling cues in the etiology and progression of NB.
Topics: Adolescent; Adrenal Gland Diseases; Adrenal Glands; Child; Child, Preschool; Gene Expression Regulation, Neoplastic; Humans; Nerve Tissue Proteins; Neural Crest; Neuroblastoma; Neurons; Paraganglioma; Stem Cells; Survival Analysis; Sympathetic Nervous System; Wnt Proteins; Wnt Signaling Pathway
PubMed: 29058015
DOI: 10.1007/s00018-017-2685-8 -
Der Internist Jan 2009Pheochromocytomas are rare, mostly benign catecholamine-producing tumors arising from the chromaffin cells of the adrenal medulla or in the paraganglia. Clinical... (Review)
Review
Pheochromocytomas are rare, mostly benign catecholamine-producing tumors arising from the chromaffin cells of the adrenal medulla or in the paraganglia. Clinical presentation is highly variable but typically with hypertension, severe headaches, palpitations and sweating. Biochemical testing by 24 h urinary fractioned metanephrines or catecholamines and plasma free metanephrines as the most sensitive screening approach, confirms the catecholamine excess. Computed tomography scan and magnetic resonance imaging of the adrenal glands and abdomen as well as functional imaging with (123)Iod-MIBG scintigraphy and (18)F-dopa positron emission tomography are used for tumor localization. Because approximately a quarter of tumors develop secondary to germ-line mutations, screening for genetic alterations is important. The therapy of choice is the endoscopic adrenal sparing surgery following preoperative alpha-blockade. Regular follow-up remains essential due to possible recurrence and malignancy.
Topics: Adrenal Gland Neoplasms; Humans; Hypertension; Pheochromocytoma
PubMed: 19099277
DOI: 10.1007/s00108-008-2196-7 -
Pathology, Research and Practice 1999Paraganglionic tissues incidentally observed in the gallbladder are presented. The patients, a 51- and a 55-year-old woman, underwent gallbladder resection for chronic...
Paraganglionic tissues incidentally observed in the gallbladder are presented. The patients, a 51- and a 55-year-old woman, underwent gallbladder resection for chronic cholecystitis with gallstones. Two and one paraganglionic tissues were observed in the subserosal connective tissue of the two gallbladders, respectively. Immunohistochemically, the chief cells were positive for chromogranin A, and the sustentacular cells were positive for S100 protein. Tyrosine hydroxylase (in two of three), dopamine beta-hydroxylase (in one of three), methionine-enkephalin (in two of three), and leucine-enkephalin (in two of three) were also positive in a small amount of the chief cells. These structures, which slightly resembled adrenal medulla or retroperitoneal paraganglia, might be misunderstood as an infiltration of primary or metastatic carcinoma into the subserosal connective tissue.
Topics: Cholecystitis; Chromogranin A; Chromogranins; Chronic Disease; Dopamine beta-Hydroxylase; Enkephalin, Leucine; Enkephalin, Methionine; Female; Gallbladder; Humans; Immunoenzyme Techniques; Middle Aged; Paraganglia, Chromaffin; S100 Proteins; Tyrosine 3-Monooxygenase
PubMed: 10605699
DOI: 10.1016/S0344-0338(99)80121-6 -
Langenbeck's Archives of Surgery Feb 2012Malignant pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare disorders arising from the adrenal gland, from the glomera along parasympathetic nerves or from... (Comparative Study)
Comparative Study Review
INTRODUCTION
Malignant pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare disorders arising from the adrenal gland, from the glomera along parasympathetic nerves or from paraganglia along the sympathetic trunk. According to the WHO classification, malignancy of PCCs and PGLs is defined by the presence of metastases at non-chromaffin sites distant from that of the primary tumor and not by local invasion. The overall prognosis of metastasized PCCs/PGLs is poor. Surgery offers currently the only change of cure. Preferably, the discrimination between malignant and benign PCCs/PGLs should be made preoperatively.
METHODS
This review summarizes our current knowledge on how benign and malignant tumors can be distinguished.
CONCLUSION
Due to the rarity of malignant PCCs/PGLs and the obvious difficulties in distinguishing benign and malignant PCCs/PGLs, any patient with a PCC/PGL should be treated in a specialized center where a multidisciplinary setting with specialized teams consisting of radiologists, endocrinologist, oncologists, pathologists and surgeons is available. This would also facilitate future studies to address the existing diagnostic and/or therapeutic obstacles.
Topics: Adrenal Gland Neoplasms; Adrenalectomy; Animals; Biopsy, Needle; Chemotherapy, Adjuvant; Diagnosis, Differential; Diagnostic Imaging; Female; Humans; Immunohistochemistry; Male; Neoplasm Staging; Paraganglioma; Pheochromocytoma; Prognosis; Radiotherapy, Adjuvant; Survival Analysis
PubMed: 22124609
DOI: 10.1007/s00423-011-0880-x -
Journal of Neurocytology Jun 1987Paraganglia of the recurrent laryngeal nerve of rats exposed to hypoxia (10 +/- 0.5% O2) for 3 weeks became enlarged in volume by 2.6-fold. The volume densities of blood...
Paraganglia of the recurrent laryngeal nerve of rats exposed to hypoxia (10 +/- 0.5% O2) for 3 weeks became enlarged in volume by 2.6-fold. The volume densities of blood vessel lumen and endothelial cells were unchanged. The enlargement of the paraganglia was mainly attributed to hypertrophy of the dense-cored vesicle-containing cell. Concerning the profile diameter of the vesicle, a unimodal distribution of dense-cored vesicle cells was found in both control and hypoxic paraganglia. The vesicle diameter increased by about 19%, whereas the numerical density of dense-cored vesicles and the vesicle volume density were unaltered after hypoxia. Recurrent laryngeal nerves assayed by a sensitive high performance liquid chromatography technique contained an average of 1.9 pmol dopamine and 1.3 pmol norepinephrine. Exposure to 2 weeks of hypoxia increased the dopamine level to 4.9 pmol, whereas the norepinephrine content was unchanged. It is suggested from this study that the catecholamines determined are housed in the paraganglia of the recurrent laryngeal nerve.
Topics: Animals; Chromatography, High Pressure Liquid; Dopamine; Hypoxia; Laryngeal Nerves; Male; Microscopy, Electron; Norepinephrine; Paraganglia, Nonchromaffin; Rats; Rats, Inbred Strains; Recurrent Laryngeal Nerve
PubMed: 3612181
DOI: 10.1007/BF01611341 -
Acta Anatomica 1995Abdominal vagal afferent fibers were selectively labeled by injecting the fluorescent carbocyanine dye DiI into the left nodose ganglion of rats. Almost all paraganglia...
Abdominal vagal afferent fibers were selectively labeled by injecting the fluorescent carbocyanine dye DiI into the left nodose ganglion of rats. Almost all paraganglia that were distributed along the five major abdominal vagal branches and their subbranches were found to be innervated by labeled vagal afferents. Laser scanning confocal microscopy with its single optical sectioning and three-dimensional reconstruction capabilities were used to analyze this innervation in more detail for paraganglia near the vagal hepatic branch and liver hilus. Furthermore, in double-labeling studies, it was demonstrated that a large percentage of the vagally innervated glomus cells were capable of catecholamine synthesis on the basis of their positive staining for tyrosine hydroxylase antibody. These findings support the concept of a chemoreceptive function for the abdominal paraganglia.
Topics: Animals; Carbocyanines; Catecholamines; Male; Microscopy, Confocal; Nerve Fibers; Neurons, Afferent; Nodose Ganglion; Paraganglia, Nonchromaffin; Rats; Rats, Sprague-Dawley; Tyrosine 3-Monooxygenase; Vagus Nerve
PubMed: 7660756
DOI: 10.1159/000147691 -
The Anatomical Record Jul 1988The topographical, ultrastructural, and histochemical features of 23 human vagal paraganglia were analyzed. Nineteen of the 23 paraganglia were found in previously...
The topographical, ultrastructural, and histochemical features of 23 human vagal paraganglia were analyzed. Nineteen of the 23 paraganglia were found in previously unreported sites; 18 of the 19 were in the cervical part of the nerve, between the carotid bifurcation and the superior thoraco-cervical inlet, and one paraganglion was located in the retrothyroidal part of the left inferior laryngeal nerve. The results of ultrastructural studies (2 cases), the histochemical and formaldehyde-induced-fluorescence studies (3 cases), and specific acetylcholinesterase activity (one case) demonstrate that these structures fulfill many of the modern criteria for paraganglionic tissue. In addition to paraganglia, single, isolated neurons or true micro-ganglia were always found along the trunk and branches of the vagus nerve when multiple sections were examined.
Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Chromaffin System; Histocytochemistry; Humans; Infant; Infant, Newborn; Microscopy, Electron; Middle Aged; Paraganglia, Chromaffin; Vagus Nerve
PubMed: 3189869
DOI: 10.1002/ar.1092210310