Abstract
Pheochromocytomas and Paragangliomas (PGL) form the group of paraganglial tumours which can occur in any paraganglia from the skull base to the pelvic floor. The terminology is not uniform. While the World Health Organization (WHO) applies pheochromocytoma exclusively to adrenal tumours, many clinicians use the term pheochromocytoma also for extra-adrenal abdominal and thoracic tumours, since by tradition pheochromocytoma is a vasoactive tumour. In contrast, head and neck paraganglioma is mostly only a space-occupying mass. The diagnosis is confirmed by both biochemical testing and radiological imaging. One third of patients with pheochromocytomas and paragangliomas are carriers of germline mutations in one of 6 genes and thus have a hereditary disorder. About 1% of Neurofibromatosis (NF) 1 patients have pheochromocytomas. All pheochromocytoma patients with NF 1 also show cutaneous lesions. About 50% of MEN2 patients harbour pheochromocytoma. The dominant lesion in this entity is Medullary Thyroid Carcinoma (MTC) occurring in up to 100% of patients. Von Hippel-Lindau disease (VHL)is found in about 20% of patients in association with pheochromocytoma. VHL is classified as type 1 predominantly without and type 2 predominantly with pheochromocytoma. Other important components of VHL are hemangioblastomas of the eye and Central Nervous System (CNS), renal clear cell carcinoma, multiple pancreatic cysts and islet cell carcinoma. PGL syndromes have been genetically characterized as PGL 1, 3 and 4 and are caused by mutations in the succinate dehydrogenase (SDH) subunit D, C and B genes, respectively (SDHD, SDHC and SDHB). Paraganglioma syndromes include predisposition to paraganglial tumours in any location, whereas PGL 3 patients mostly show only head and neck paragangliomas. All syndromes associated with paraganglial tumours are autosomal dominantly transmitted, but patients with SDHD mutations develop tumours only if they inherit the mutation from the father. Familial paraganglial tumours are characterized by younger age at diagnosis and more frequently multifocal and extra-adrenal abdominal pheochromocytomas. Patients with PGL 4 and less frequently VHL, are particularly predisposed to malignant pheochromocytoma. Endoscopic surgery is the primary treatment for pheochromocytoma. For malignant cases, chemotherapeutic as well as radionuclear approaches are available. No specific treatment has been proposed for prevention of the disease in inherited disorders. Thus, early diagnosis and regular follow-up are the only means for a better outcome.
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Zak F, Lawson W 1982 Anatomy and topography. In The Paraganglionic Chemoreceptor System. Springer-Verlag.
Baysal BE, 2002 Hereditary paraganglioma targets diverse paraganglia. J Med Genet 39: 617–622.
Neumann H 2008 Pheochromocytoma. In Harrison’s Principles of Internal Medicine, The McGraw-Hill Companies, Inc; New York
DeLellis RA, Lloyd RV, Heitz PU, Eng C, 2004 World Health Organization (2004) WHO Classification of Tumours, Pathology and genetics of tumours of endocrine organs Lyon, IARC Press.
Yeo H, Roman S, 2005 Pheochromocytoma and functional paraganglioma. Curr Opin Oncol 17: 13–18.
Proye C, Vix M, Goropoulos A, Kerlo P, Lecomte-Houcke M, 1992 High incidence of malignant pheochromocytoma in a surgical unit. 26 cases out of 100 patients operated from 1971 to 1991. J Endocrinol Invest 15: 651–663.
Melicow MM, 1977 One hundred cases of pheochromocytoma (107 tumours) at the Columbia-Presbyterian Medical Center, 1926–1976: a clinicopathological analysis. Cancer 40: 1987–2004.
Thompson LD, 2002 Pheochromocytoma of the Adrenal gland Scaled Score (PASS) to separate benign from malignant neoplasms: a clinicopathologic and immunophenotypic study of 100 cases. Am J Surg Pathol 26: 551–566.
Thouennon E, Elkahloun AG, Guillemot J, et al, 2007 Identification of potential gene markers and insights into the pathophysiology of pheochromocytoma malignancy. J Clin Endocrinol Metab 92: 4865–4872.
McNicol AM, 2006 Histopathology and immunohisto-chemistry of adrenal medullary tumours and paragangliomas. Endocr Pathol 17: 329–336.
Neumann HP, Bausch B, McWhinney SR, et al, 2002 Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 346: 1459–1466.
Neumann HP, Pawlu C, Peczkowska M, et al, 2004 Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. [erratum appears in JAMA. 2004 Oct 13;292(14): 1686]. JAMA 292: 943–951.
Peczkowska M, Cascon A, Prejbisz A, et al, 2008 Extra-adrenal and adrenal pheochromocytomas associated with a germline SDHC mutation. Nat Clin Pract Endocrinol Metab 4: 111–115.
Amar L, Bertherat J, Baudin E, et al, 2005 Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol 23: 8812–8818.
Fränkel F, 1886 Ein Fall von doppelseitigem, völlig latent verlaufenen Nebennierentumor und gleichzeitiger Nephritis mit Veränderungen am Circulationsapparat und Retinits. Virchows Archiv für Pathologie, Anatomie und Physiologie 103: 244–263.
Neumann HP MD, Alexander Vortmeyer, Dieter Schmidt, et al, 2007 Evidence for MEN 2 in the Original Description of Classic Pheochromocytoma. N Engl J Med 357: 1311–1315.
Suzuki S, 1910 Über zwei Tumoren aus Nebennierenmark-gewebe. Berliner Klinische Wochenschrift 47: 1623.
Neumann HP, Berger DP, Sigmund G, et al, 1993 Pheochromocytomas, multiple endocrine neoplasia type 2, and von Hippel-Lindau disease. N Engl J Med 329: 1531–1538.
Baysal BE, Ferrell RE, Willett-Brozick JE, et al, 2000 Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 287: 848–851.
Astuti D, Latif F, Dallol A, et al, 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.
Mannelli M, Ercolino T, Giache V, Simi L, Cirami C, Parenti G, 2007 Genetic screening for pheochromocytoma: should SDHC gene analysis be included? J Med Genet 44: 586–587.
Pigny P, Vincent A, Cardot Bauters C, et al, 2008 Paraganglioma after maternal transmission of a succinate dehydrogenase gene mutation. J Clin Endocrinol Metab 93: 1609–1615.
Neumann HP, Erlic Z, 2008 Maternal Transmission of Symptomatic Disease with SDHD Mutation: Fact or Fiction? J Clin Endocrinol Metab 93: 1573–1575.
Opocher G, Schiavi F, Iacobone M, et al, 2006 Familial nonsyndromic pheochromocytoma. Ann N Y Acad Sci 1073: 149–155.
Dahia PL, Hao K, Rogus J, et al, 2005 Novel pheochromocytoma susceptibility loci identified by integrative genomics. Cancer Res 65: 9651–9658.
Wallace MR, Marchuk DA, Andersen LB, et al, 1990 Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science 249: 181–186.
Riccardi VM, 1981 Von Recklinghausen neurofibromatosis. N Engl J Med 305: 1617–1627.
Opocher G, Conton P, Schiavi F, Macino B, Mantero F, 2005 Pheochromocytoma in von Hippel-Lindau disease and neurofibromatosis type 1. Fam Cancer 4: 13–16.
Bausch B, Borozdin W, Neumann HPH, 2006 European-American Pheochromocytoma Study G. Clinical and genetic characteristics of patients with neurofibromatosis type 1 and pheochromocytoma. N Engl J Med 354: 2729–2731.
Machens A, Brauckhoff M, Holzhausen HJ, Thanh PN, Lehnert H, Dralle H, 2005 Codon-specific development of pheochromocytoma in multiple endocrine neoplasia type 2. J Clin Endocrinol Metab 90: 3999–4003.
Quayle FJ, Fialkowski EA, Benveniste R, Moley JF, 2007 Pheochromocytoma penetrance varies by RET mutation in MEN 2A. Surgery 142: 800–805.
Neumann HP, Wiestler OD, 1991 Clustering of features of von Hippel-Lindau syndrome: evidence for a complex genetic locus. [see comment]. Lancet 337: 1052–1054.
Latif F, Tory K, Gnarra J, et al, 1993 Identification of the von Hippel-Lindau disease tumor suppressor gene. [see comment]. Science 260: 1317–1320.
Maher ER, Webster AR, Richards FM, et al, 1996 Phenotypic expression in von Hippel-Lindau disease: correlations with germline VHL gene mutations. J Med Genet 33: 328–332.
Eng C, Kiuru M, Fernandez MJ, Aaltonen LA, 2003 A role for mitochondrial enzymes in inherited neoplasia and beyond. Nat Rev Cancer 3: 193–202.
Baysal BE, Lawrence EC, Ferrell RE, 2007 Sequence variation in human succinate dehydrogenase genes: evidence for long-term balancing selection on SDHA. BMC Biol 5: 12.
Mariman EC, van Beersum SE, Cremers CW, Struycken PM, Ropers HH, 1995 Fine mapping of a putatively imprinted gene for familial non-chromaffin paragangliomas to chromosome 11q13. 1: evidence for genetic heterogeneity. Hum Genet 95: 56–62.
Reisch N, Walz MK, Erlic Z, Neumann HP, 2009 [Pheochromocytoma — still a challenge]. Der Internist 50: 27–35
Benn DE, Gimenez-Roqueplo AP, Reilly JR, et al, 2006 Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. J Clin Endocrinol Metab 91: 827–836.
Baysal BE, Willett-Brozick JE, Filho PA, Lawrence EC, Myers EN, Ferrell RE, 2004 An Alu-mediated partial SDHC deletion causes familial and sporadic paraganglioma. J Med Genet 41: 703–709.
Schiavi F, Boedeker CC, Bausch B, et al, 2005 Predictors and prevalence of paraganglioma syndrome associated with mutations of the SDHC gene. JAMA 294: 2057–2063.
Vanharanta S, Buchta M, McWhinney SR, et al, 2004 Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma. Am J Hum Genet 2004;74: 153–159.
McWhinney SR, Pasini B, Stratakis CA, 2007 Familial gastrointestinal stromal tumours and germ-line mutations. N Engl J Med 357: 1054–1056.
Plouin PF, Degoulet P, Tugaye A, Ducrocq MB, Menard J, 1981 [Screening for phaeochromocytoma: in which hypertensive patients? A semiological study of 2585 patients, including 11 with phaeochromocytoma (author’s transl)]. La Nouvelle presse medicale 10: 869–872.
Baguet JP, Hammer L, Mazzuco TL, Chabre O, et al, 2004 Circumstances of discovery of phaeochromocytoma: a retrospective study of 41 consecutive patients. Eur J Endocrinol 150: 681–686.
Mannelli M, Ianni L, Cilotti A, Conti A, 1999 Pheochro-mocytoma in Italy: a multicentric retrospective study. Eur J Endocrinol 141: 619–624.
Proye C, Fossati P, Fontaine P, et al, 1986 Dopamine-secreting pheochromocytoma: an unrecognized entity? Classification of pheochromocytomas according to their type of secretion. Surgery 100: 1154–1162.
Manger WM, Eisenhofer G, 2004 Pheochromocytoma: diagnosis and management update. Current Hypertens Rep 6: 477–484.
Young WF Jr 2008 Endocrine hypertension. In Williams Textbook of Endocrinology, Philadelphia, PA, Saunders Elsevier.
Mariola Peczkowska, Zoran Erlic, Michael M. Hoffmann, et al, Impact of Screening Kindreds for SDHD p. Cys11X as a Common Mutation Associated with Paraganglioma Syndrome Type 1. J Clin Endocrinol Metab 93: 4818-4825.
Lenders JW, Pacak K, Walther MM, et al, 2002 Biochemical diagnosis of pheochromocytoma: which test is best? JAMA 287: 1427–1434.
Eisenhofer G, Lenders JW, Goldstein DS, et al, 2005 Pheochromocytoma catecholamine phenotypes and prediction of tumor size and location by use of plasma free metanephrines. Clin Chem 51: 735–744.
Ilias I, Pacak K, 2004 Current approaches and recommended algorithm for the diagnostic localization of pheochromocytoma. J Clin Endocrinol Metab 89: 479–491.
van der Harst E, de Herder WW, Bruining HA, et al, 2001 [(123)I]metaiodobenzylguanidine and [(111)In]octreotide uptake in begnign and malignant pheochromocytomas. J Clin Endocrinol Metab 86: 685–693.
Furuta N, Kiyota H, Yoshigoe F, Hasegawa N, Ohishi Y, 1999 Diagnosis of pheochromocytoma using [123I]-compared with [131I]-metaiodobenzylguanidine scintigraphy. Int J Urol 6: 119–124.
Hoegerle S, Ghanem N, Altehoefer C, et al, 2003 18F-DOPA positron emission tomography for the detection of glomus tumours. Eur J Nucl Med Mol Imaging 230: 689–694.
Hoegerle S, Nitzsche E, Altehoefer C, et al, 2002 Pheochromocytomas: detection with 18F DOPA whole body PET—initial results. Radiology 222: 507–512.
Pacak K, 2007 Preoperative management of the pheochromocytoma patient. J Clin Endocrinol Metab 92: 4069–4079.
Walz MK, Peitgen K, Walz MV, et al, 2001 Posterior retroperitoneoscopic adrenalectomy: lessons learned within five years. World J Surg 25: 728–734.
Walz MK, Petersenn S, Koch JA, Mann K, Neumann HP, Schmid KW, 2005 Endoscopic treatment of large primary adrenal tumours. Br J Surg 92: 719–723.
Walz MK, Alesina PF, Wenger FA, et al, 2006 Laparoscopic and Retroperitoneoscopic Treatment of Pheochromocytomas and Retroperitoneal Paragangliomas: Results of 161 Tumours in 126 Patients. World J Surg 30: 1–10.
Barczynski M, Konturek A, Golkowski F, et al, 2007 Posterior retroperitoneoscopic adrenalectomy: a comparison between the initial experience in the invention phase and introductory phase of the new surgical technique. World J Surg 31: 65–71.
Yip L, Lee JE, Shapiro SE, et al, 2004 Surgical management of hereditary pheochromocytoma. J Am Coll Surg 198: 525–534
Walz MK, Peitgen K, Diesing D, et al, 2004 Partial versus total adrenalectomy by the posterior retroperitoneoscopic approach: early and long-term results of 325 consecutive procedures in primary adrenal neoplasias. World J Surg 28: 1323–1329.
Walz MK, Peitgen K, Neumann HP, Janssen OE, Philipp T, Mann K, 2002 Endoscopic treatment of solitary, bilateral, multiple, and recurrent pheochromocytomas and paragangliomas. World J Surg 26: 1005–1012.
Safford SD, Coleman RE, Gockerman JP, et al, 2003 Iodine -131 metaiodobenzylguanidine is an effective treatment for malignant pheochromocytoma and paraganglioma. Surgery 134: 956–962.
Fitzgerald PA, Goldsby RE, Huberty JP, et al, 2006 Malignant pheochromocytomas and paragangliomas: a phase II study of therapy with high-dose 131I-metaiodobenzylguanidine (131I-MIBG). Ann NY Acad Sci 1073: 465–490.
Forrer F, Riedweg I, Maecke HR, Mueller-Brand J, 2008 Radiolabeled DOTATOC in patients with advanced paraganglioma and pheochromocytoma. Q J Nucl Med Mol Imaging 52: 334–340.
Wehrmann C, Senftleben S, Zachert C, Muller D, Baum RP, 2007 Results of individual patient dosimetry in peptide receptor radionuclide therapy with 177Lu DOTA-TATE and 177Lu DOTA-NOC. Cancer Biother Radiopharm 22: 406–416.
Manger WM, Gifford RW, 2002 Pheochromocytoma. J Clin Hypertens 4: 62–72.
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Erlic, Z., Neumann, H.P.H. Familial pheochromocytoma. Hormones 8, 29–38 (2009). https://doi.org/10.14310/horm.2002.1219
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DOI: https://doi.org/10.14310/horm.2002.1219