An Update on the Histology of Pheochromocytomas: How Does it Relate to Genetics? (original) (raw)
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Molecular Genetic Alterations in Adrenal and Extra-Adrenal Pheochromocytomas and Paragangliomas
Endocrine Pathology, 2003
Pheochromocytomas and paragangliomas are neuroendocrine neoplasias of neural crest origin. Genetic mutations that are characterized in other human neoplasms are rarely seen in these tumors. About 10% of the patients with pheochromocytomas and paragangliomas present with a family history of von Hippel-Lindau disease (VHL), Multiple endocrine neoplasia type 2 (MEN2), one of the three familial paraganglioma syndromes (PGL; PGL1, PGL3, PGL4), or neurofibromatosis type 1 (NF1). In an even higher percentage, a genetic predisposition is involved in the development of these tumors. The genes of hereditary tumor syndromes such as the aforementioned ones are also ideal to study the molecular pathogenesis in the sporadic counterparts. Many studies have been undertaken to identify important secondary genetic events that contribute to the tumorigenesis of pheochromocytoma or paraganglioma, but a comprehensive review of these data is lacking. Recent findings of CGH and LOH studies provided new starting points to unravel the pathogenesis and progression of these tumors. This review presents an overview of our current understanding of the molecular pathogenesis of pheochromocytoma and paraganglioma.
Pheochromocytomas and Paragangliomas: Clinical and Genetic Approaches
Frontiers in Endocrinology, 2015
Pheochromocytomas (PCCs) and paragangliomas (PGLs) are neuroendocrine tumors derived from the chromaffin tissue. Diagnosis of these tumors is extremely important as they are linked to the hypertension syndrome with great cardiovascular morbidity and mortality. A great majority of PCCs and PGLs are sporadic and benign tumors; however, the classic idea of 10% exception of these features is changing. The description of new genes linked to familial forms of PCC/PGLs, such as succinate dehydrogenase (SDH) complex subunits, KIF1Bβ, EGLN1, TMEM127, and MAX, added to the well-known PCC familial syndrome (MEN2, VHL, and neurofibromatosis type 1) presents new challenges for diagnosis. In this review, we discuss the diversity of clinical and genetic approaches to this syndrome as well the diverse criteria that should guide genetic investigation.
Recent Advances in the Genetics of Pheochromocytomas and Paragangliomas
2016
Paragangliomas and pheochromocytomas are rare neuroendocrine tumors, which secrete catecholamines, with the same embryological origin from the neural crest cells. Pheochromocytomas develop from the adrenal medulla, while paragangliomas are extraadrenal tumors, evolving from the autonomic sympathetic and parasympathetic nervous chains. In the last 10 years, molecular medicine has discovered novelties in the understanding of genetics of these tumors. Although the majority of these tumors occur sporadically, recent medical discoveries have indicated that approximately 30-40% of these tumors are associated with an inherited mutation. In addition to this, developments in molecular pathology of pheochromocytomas and paragangliomas will provide the key to target specifi c cellular markers, assuring a personalised therapy. In this article we have reviewed the current medical literature, in order to summarise the most important aspects of genetics and clinical features of pheochromocytomas a...
Clinical Presentation and Penetrance of Pheochromocytoma/Paraganglioma Syndromes
The Journal of Clinical Endocrinology & Metabolism, 2006
Ph: 61 2 9926 7267 Fax: 61 2 9926 8523 Key Words: pheochromocytoma, paraganglioma, succinate dehydrogenase subunit B (SDHB), succinate dehydrogenase subunit D (SDHD). Abbreviated title: Clinical presentation of Pheochromocytoma/ Paraganglioma syndromes Word Count (Text excluding Abstract): 3,294 ABSTRACT Context The identification of succinate dehydrogenase (SDH) gene mutations in Pheochromocytoma/Paraganglioma syndromes has necessitated clear elucidation of genotype-phenotype associations. Objective To determine genotype-phenotype associations in a cohort of patients with Pheochromocytoma/Paraganglioma syndromes and succinate dehydrogenase subunit B (SDHB) or subunit D (SDHD) mutations. Design, Setting and Participants The International SDH Consortium studied 116 individuals (83 affected and 33 clinically unaffected) from 62 families with Pheochromocytoma/Paraganglioma syndromes and SDHB or SDHD mutations. Clinical Main Outcome Measures Data was collected on patients with pheochromocytomas and/or paragangliomas, with respect to onset of disease, diagnosis, genetic testing, surgery, pathology and disease progression. Clinical features were evaluated for evidence of genotype-phenotype associations and penetrance was determined. Results SDHB mutation carriers were more likely than SDHD mutation carriers to develop extra-adrenal pheochromocytomas and malignant disease, whereas SDHD mutation carriers had a greater propensity to develop head and neck paragangliomas and 1 Husebye ES, Eng C, Maher ER 2001 Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet 69:49-54. Erratum in: Am J Hum Genet 2002, 70:565. 4 Muller U, Troidl C and Niemann S 2005 SDHC mutations in hereditary paraganglioma/pheochromocytoma. Familial Cancer 4:9-12 5 Baysal BE, Willett-Brozick JE, Filho PAA, Lawrence EC, Myers EN, Ferrell RE 2004 An Alu-mediated partial SDHC deletion causes familial and sporadic paraganglioma J Med Genet 41:703-709.
Pitfalls in Genetic Analysis of Pheochromocytomas/Paragangliomas-Case Report
The Journal of Clinical Endocrinology & Metabolism, 2014
Context: About 35% of patients with pheochromocytoma/paraganglioma carry a germline mutation in one of the 10 main susceptibility genes. The recent introduction of next-generation sequencing will allow the analysis of all these genes in one run. When positive, the analysis is generally unequivocal due to the association between a germline mutation and a concordant clinical presentation or positive family history. When genetic analysis reveals a novel mutation with no clinical correlates, particularly in the presence of a missense variant, the question arises whether the mutation is pathogenic or a rare polymorphism. Objective: We report the case of a 35-year-old patient operated for a pheochromocytoma who turned out to be a carrier of a novel SDHD (succinate dehydrogenase subunit D) missense mutation. With no positive family history or clinical correlates, we decided to perform additional analyses to test the clinical significance of the mutation. Methods: We performed in silico analysis, tissue loss of heterozygosity analysis, immunohistochemistry, Western blot analysis, SDH enzymatic assay, and measurement of the succinate/fumarate concentration ratio in the tumor tissue by tandem mass spectrometry. Results: Although the in silico analysis gave contradictory results according to the different methods, all the other tests demonstrated that the SDH complex was conserved and normally active. We therefore came to the conclusion that the variant was a nonpathogenic polymorphism. Conclusions: Advancements in technology facilitate genetic analysis of patients with pheochromocytoma but also offer new challenges to the clinician who, in some cases, needs clinical correlates and/or functional tests to give significance to the results of the genetic assay.
Clinical and Translational Oncology
Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that arise from chromaffin cells of the adrenal medulla and the sympathetic/parasympathetic neural ganglia, respectively. The heterogeneity in its etiology makes PPGL diagnosis and treatment very complex. The aim of this article was to provide practical clinical guidelines for the diagnosis and treatment of PPGLs from a multidisciplinary perspective, with the involvement of the Spanish Societies of Endocrinology and Nutrition (SEEN), Medical Oncology (SEOM), Medical Radiology (SERAM), Nuclear Medicine and Molecular Imaging (SEMNIM), Otorhinolaryngology (SEORL), Pathology (SEAP), Radiation Oncology (SEOR), Surgery (AEC) and the Spanish National Cancer Research Center (CNIO). We will review the following topics: epidemiology; anatomy, pathology and molecular pathways; clinical presentation; hereditary predisposition syndromes and genetic counseling and testing; diagnostic procedures, including biochemical test...
[Hereditary pheochromocytoma and paraganglioma]
2012
Pheochromocytomas and paragangliomas are tumors arising from chromaffin cells. These tumors produce catecholamines and are typically found with symptoms and signs that may include hypertension (persistent or episodic), palpitations, headache and sweating. So far, 10 different genes have been associated with both tumors and other genes are expected to be detected. Pheochromocytoma and paraganglioma can occur as a part of genetic syndromes - familial paragangliomas (SDH genes, SDHAF2 gene), von Hippel-Lindau syndrome (VHL gene), multiple endocrine neoplasia type 2 (RET gene), and neurofibromatosis type 1 (NF1 gene). These tumors may be the first and only manifestation of these genetic syndromes. Patients with SDHB mutations are at high risk to develop malignant disease and unfortunately current therapeutic options for malignant form of disease are poor. Genetic testing plays a key role in the management of these tumors and therefore not only index patients with pheochromocytoma but al...