title: Metastatic pheochromocytoma and paraganglioma.
abstract: BACKGROUND
  Metastatic pheochromocytomas (PCs) and paragangliomas (PGLs) are rare neuroendocrine tumours with a strong genetic background.
  
  
  METHODS
  We searched the PubMed database through February 2015 to identify studies characterizing metastatic PCs/PGLs as well as currently established and evolving therapies.
  
  
  RESULTS
  Large size tumours (> 5 cm), PASS score > 6 and Ki-67 labelling index > 3% are the most robust indices of metastatic PCs/PGLs albeit with great variability. Germline succinate dehydrogenase complex, subunit B (SDHB) mutation constitutes the main reliable molecular predictor of malignancy. Plasma and urinary methoxytyramine are the biochemical markers characterizing metastatic PCs/PGLs along with evolving molecular markers such as miRNAs and SNAIL. Conventional imaging is used for tumour localization, whereas (18)F-FDG-PET for staging of metastatic PCs/PGLs especially those related to SDHB gene mutations. In addition, (68)Ga-DOTATATE PET/CT is emerging as a highly sensitive alternative. Surgery remains the gold standard treatment in reducing tumour bulk and/or controlling the clinical syndrome. Treatment with (131)I-MIBG or radiolabelled somatostatin analogues is considered for unresectable disease. Conventional chemotherapy is reserved for more advanced and refractory to other therapies disease although new schemes are currently evolving. Recent genetic studies have highlighted a number of pathways involved in PCs/PGLs pathogenesis directing towards the use of targeted therapies which have still to be validated in clinical practice.
  
  
  CONCLUSIONS
  Metastatic PCs/PGLs remain an orphan disease that is only curable by surgery. However, advances in genomic analyses have improved the pathogenesis of these tumours and may lead to effective and more personalized treatments in the near future.
authors.affiliation: Department of Pathophysiology, Medical School, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Anna
authors.initials: A
authors.lastname: Angelousi
authors.affiliation: Department of Biochemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Evanthia
authors.initials: E
authors.lastname: Kassi
authors.affiliation: Department of Surgery, George Gennimatas Hospital, Athens, Greece.
authors.forename: Georgios
authors.initials: G
authors.lastname: Zografos
authors.affiliation: Department of Pathophysiology, Medical School, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Gregory
authors.initials: G
authors.lastname: Kaltsas
mesh_terms: D019797:3-Iodobenzylguanidine; D000310:Adrenal Gland Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D019788:Fluorodeoxyglucose F18; D006801:Humans; D064847:Multimodal Imaging; D009154:Mutation; D010235:Paraganglioma / Q000175:diagnosis / Q000235:genetics / Q000556:secondary* / Q000628:therapy; D010673:Pheochromocytoma / Q000175:diagnosis / Q000235:genetics / Q000556:secondary* / Q000628:therapy; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D013385:Succinate Dehydrogenase / Q000235:genetics; D014057:Tomography, X-Ray Computed
chemical_list: D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D019797:3-Iodobenzylguanidine; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase
keywords: MIBG; Metastatic paragangliomas; SDHB mutation; metastatic pheochromocytomas; temozolomide