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Neuro-Endocrine/Endocrine system: Phaeochromocytoma

Written2003-01Anne-Paule Gimenez-Roqueplo
Département de Génétique Moléculaire, Hôpital Européen Georges Pompidou, 20-40, rue Leblanc, 75908 Paris cedex 15, France

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ICD-Morpho 8700/0 Benign Pheochromocytoma
Atlas_Id 5026
Phylum Neuro-Endocrine/Endocrine system: Adrenal gland::Pheochromocytoma (Functional paraganglioma)
WHO/OMS Classification Neuro-Endocrine/Endocrine system
Other namesCatecholamine-secreting paraganglioma
Functional paraganglioma
Note Usually, the term phaeochromocytoma designe secreting adrenal medulla tumor. An extraadrenal tumor is indicated by the term catecholamine-secreting paraganglioma.

Clinics and Pathology

Note Neuroendocrine tumours arise from neuroectodermal chromaffin tissue, usually develop within the adrenal medulla but could develop in extraadrenal sympathetic ganglia in 10 % of cases. Phaechromocytomas secrete catecholamines (epinephrine, norepinephrine, dopamine) in the circulation and could induce severe lethal cardiovascular and cerebrovascular complications.
They are located in the abdomen and in the pelvis (adrenal medulla, organ of Zuckerkandl, urinary bladder, paraganglia chromaffin cells in association with nerves and plexus). In rare cases, they could develop in the mediastinum (chest, pericardium, thorax) or in the neck (carotid body) and in the head (glomus jugulare and tympanicum). Usually, the paragangliomas located in the neck and in the head are non functional.
Phenotype / cell stem origin Crest neural cells
Etiology Phaeochromocytoma is an inherited form of cancer in 10% to 25% of cases. In familial cases, pheochromocytoma is a component of one of the four following autosomal dominant syndromic diseases, Multiple Endocrine Neoplasia type 2 (MEN2), Von-Hippel-Lindau disease (VHL), Hereditary paraganglioma syndrome (PGL) and Neurofibromatosis type 1 (NF1). In 75 to 90% cases, it is a sporadic or a non syndromic disease of an unknown etiology.
Epidemiology The annual incidence is estimated at 1/10 000.
Clinics The clinical manifestations are commonly paroxystics and result from catecholamine secretion: blood pressure changes (hypertension ± hypotension, orthostatic hypotension, hypertension induced by postural change or by the palpation of the mass), tachycardia, excessive sweating, pallor of face, headaches, etc . The diagnosis is given by the elevation of the 24-hour urinary total metanephrine-(metanephrine plus normetanephrine)-to-creatinine ratio and by the location of the tumor by imagery tests (computed axial tomography, magnetic resonnance imaging, scintigraphy with 131I-MIBG, somatostatin receptor scintigraphy).
Treatment The treatment is the surgical removal of the tumor in a reference center. The patient must be prepared by a preoperative alpha blockade in order to prevent severe hypertensive crises and complications at the time of surgery. The treatment of recurrence or metastases is surgery to reduce tumor mass and/or alternative therapy as irradiation with large doses of 131I-MIBG or radiotherapy of bones metastases.
Evolution Usually phaeochromocytomas are benign tumors but they could be malignant (lymph nodes, bone or visceral metastases) in 10% of cases with recurrence and distant metastases. Tumor recurrence may occur months or years following the initial surgery.


Allelic losses at chromosome 1p, 3p, 17p, and 22q have been reported in sporadic and familial forms of phaeochromocytomas and at chromosome 11q in head and neck paragangliomas.

Genes involved and Proteins

Note 271 patients with an apparently sporadic phaeochromocytoma, and identified 66 patients with a germline mutations (24%) have been tested. Of these 66, 11 patients had mutations of SDHD (4%), 12 of SDHB (4.5%), 13 of RET (4.8%) and 30 of VHL (11.3%) genes. The genetic testing of all patients with phaeochromocytoma is important to identify genetic defects which are relatively frequents even in apparently sporadic tumours, to organize the clinical management of the patients with an inherited form of the disease and to propose a presymptomatic familial genetic testing.
Gene NameSDHB (succinate dehydrogenase complex II, subunit B, iron-sulfur protein or IP)
Location 1p36.13
Dna / Rna 8 exons, 1100 bp, 35.45 kb.
Protein The subunit B protein or iron-sulfur protein (280 amino acids, 31.62 kDa), which binds three different iron-sulfur clusters, is directly involved in the catalytic activity of succinate dehydrogenase (mitochondrial complex II).
Germinal mutation Germline mutations cause hereditary paraganglioma, non-familial paraganglioma, familial and sporadic pheochromocytomas. Different germline mutations have been reported. Mutations in SDHB have been also published in cases of sporadic and familial malignant pheochromocytomas. Some tumors display a second hit with the loss of 1p chromosome containing the wild type allele of SDHB gene. As in SDHD-inherited tumors, the inactivation of SDHB protein induces a complete loss of succinate deshydrogenase activity in the tumoral tissues and an activation of hypoxic-angiogenic pathway.

Gene NameVHL (von Hippel-Lindau tumor suppressor)
Location 3p25.3
Dna / Rna 3 exons, 4862 bp, 12,37 kb
Protein The pVHL (213 amino acids, 24.15kDa) is a tumor suppressor protein which forms a multimeric complex with elongin B, elongin C and cullin 2. It is involved in several processes including cell cycle control, control of extracellular matrix, mRNA stability but its main function is the regulation of hypoxia-inducible gene expression and the negative regulation of angiogenesis via VEGF, HIF and EPAS. The VHL disease predispose to the development of various tumors. Pheochromocytoma occurs in the type 2 of the disease.
Germinal mutation Germline mutations of VHL gene have been identified in >500 kindreds. For the Von Hippel-Lindau (VHL) type 2, the mutations are missense mutations with recurrent mutations at codon 98 (Y98H), 167 (R167Q) and188 (L188V).

Gene NameRET (REarranged during Transfection)
Location 10q11.21
Dna / Rna 21 exons, 53.3kb
Protein The RET protein (1114 amino acids, 124.32 kDa) is a receptor tyrosine kinase which is expressed in derivatives of neural-crest cells. The first identified ligand is the glial-derived neurotropic factor (GDNF). The activating mutations of proto-oncogene RET, which constitutively activate the kinase receptor, induce three different subtypes of multiple endocrine neoplasia II (MEN2). Phaeochromocytoma occurs in MEN2A (in association with medullary thyroid carcinoma and hyperparathyroidism) and in MEN2B (in association with medullar thyroid carcinoma, marfanoid habitus, mucosal neuromas and ganglioneuromatosis of the gastrointestinal tract). In MEN2A, the mutations are principally located in the cystein-rich domain in affecting one important cystein residue (in exon 10 the Cys609, Cys610, Cys618 and Cys620) in particular the codon Cys634 in exon 11, which are significantly associated with phaeochromocytoma development, and induce a RET homodimerization. The MEN2B is caused by mutation in the tyrosine kinase domain and principally by the M918T mutation (95% of cases) which activates the kinase activity. The identification of a MEN2 carrier by genetic testing is an indication to propose a prophylactic thyroidectomy.

Gene NameSDHD (succinate dehydrogenase complex II, subunit D, integral membrane protein)
Location 11q23.1
Dna / Rna 4 exons, 1313 bp, 131.25 kb
Protein The complex II (succinate-ubiquinone oxidoreductase) is a key component of the mitochondrial respiratory chain and the tricarboxylic acid cycle. It is involved in the oxidation of succinate (succinate + ubiquinone = fumarate + ubiquinol) and carries electrons from FADH to CoQ. It is composed of four nuclear-encoded subunits.
The subunit D protein or small subunit (cybS) (159 amino acids, 17.43 kDa) is one of the two integral membrane proteins anchoring the complex to membrane. The inactivation of SDHD protein in tumors, resulting of a germline SDHD mutation and a 11q LOH at tumoral level, induces the complete loss of succinate deshydrogenase activity.
Germinal mutation Germline SDHD mutations are mainly associated with head and/or neck paragangliomas but several SDHD mutations have been reported in non familial and familial pheochromocytoma. Different types of mutations are described: false-sense mutations, insertions and deletions leading to protein truncation and missense mutations.

Gene NameNF1 (neurofibromin 1)
Location 17q11.2
Dna / Rna 57 exons, 8959 bp, 279.3 kb
Protein The neurofibromin 1 (2839 amino acids, 319.4 kDa) is a GTPase activating protein. In Von Recklinghausen neurofibromatosis or neurofibromatosis type 1, the risk of phaeochromocytoma is very low (<1%). The diagnosis of NF1 is essentially clinical (café au lait spots, neurofibromas, Lisch nodules, Crowe's sign, glioma of optic nerve, bone anomalies, positive family history, .. ). The genetic testing is difficult due to the large size of the gene and the absence of an hot-spot region of mutations.
Germinal mutation Nucleotide substitutions, deletions or insertions have been described.


Germline SDHD mutation in familial phaeochromocytoma.
Astuti D, Douglas F, Lennard TW, Aligianis IA, Woodward ER, Evans DG, Eng C, Latif F, Maher ER
Lancet. 2001 ; 357 (9263) : 1181-1182.
PMID 11323050
Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma.
Astuti D, Latif F, Dallol A, Dahia PL, Douglas F, George E, Sköldberg F, Husebye ES, Eng C, Maher ER
American journal of human genetics. 2001 ; 69 (1) : 49-54.
PMID 11404820
Hereditary paraganglioma targets diverse paraganglia.
Baysal BE
Journal of medical genetics. 2002 ; 39 (9) : 617-622.
PMID 12205103
Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas.
Baysal BE, Willett-Brozick JE, Lawrence EC, Drovdlic CM, Savul SA, McLeod DR, Yee HA, Brackmann DE, Slattery WH 3rd, Myers EN, Ferrell RE, Rubinstein WS
Journal of medical genetics. 2002 ; 39 (3) : 178-183.
PMID 11897817
Sporadic and familial pheochromocytomas are associated with loss of at least two discrete intervals on chromosome 1p.
Benn DE, Dwight T, Richardson AL, Delbridge L, Bambach CP, Stowasser M, Gordon RD, Marsh DJ, Robinson BG
Cancer research. 2000 ; 60 (24) : 7048-7051.
PMID 11156410
Guidelines for diagnosis and therapy of MEN type 1 and type 2.
Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C, Conte-Devolx B, Falchetti A, Gheri RG, Libroia A, Lips CJ, Lombardi G, Mannelli M, Pacini F, Ponder BA, Raue F, Skogseid B, Tamburrano G, Thakker RV, Thompson NW, Tomassetti P, Tonelli F, Wells SA Jr, Marx SJ
The Journal of clinical endocrinology and metabolism. 2001 ; 86 (12) : 5658-5671.
PMID 11739416
Identification of novel SDHD mutations in patients with phaeochromocytoma and/or paraganglioma.
Cascon A, Ruiz-Llorente S, Cebrian A, Telleria D, Rivero JC, Diez JJ, Lopez-Ibarra PJ, Jaunsolo MA, Benitez J, Robledo M
European journal of human genetics : EJHG. 2002 ; 10 (8) : 457-461.
PMID 12111639
Differential loss of chromosome 11q in familial and sporadic parasympathetic paragangliomas detected by comparative genomic hybridization.
Dannenberg H, de Krijger RR, Zhao J, Speel EJ, Saremaslani P, Dinjens WN, Mooi WJ, Roth J, Heitz PU, Komminoth P
The American journal of pathology. 2001 ; 158 (6) : 1937-1942.
PMID 11395368
Pheochromocytoma--death of an axiom.
Dluhy RG
The New England journal of medicine. 2002 ; 346 (19) : 1486-1488.
PMID 12000821
Loss of heterozygosity on the short arm of chromosome 1 in pheochromocytoma and abdominal paraganglioma.
Edström Elder E, Nord B, Carling T, Juhlin C, Bäckdahl M, Höög A, Larsson C
World journal of surgery. 2002 ; 26 (8) : 965-971.
PMID 12045857
Genotype-phenotype correlation in von Hippel-Lindau syndrome.
Friedrich CA
Human molecular genetics. 2001 ; 10 (7) : 763-767.
PMID 11257110
Functional consequences of a SDHB gene mutation in an apparently sporadic pheochromocytoma.
Gimenez-Roqueplo AP, Favier J, Rustin P, Rieubland C, Kerlan V, Plouin PF, Rötig A, Jeunemaitre X
The Journal of clinical endocrinology and metabolism. 2002 ; 87 (10) : 4771-4774.
PMID 12364472
Somatic and occult germ-line mutations in SDHD, a mitochondrial complex II gene, in nonfamilial pheochromocytoma.
Gimm O, Armanios M, Dziema H, Neumann HP, Eng C
Cancer research. 2000 ; 60 (24) : 6822-6825.
PMID 11156372
The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2.
Gutmann DH, Aylsworth A, Carey JC, Korf B, Marks J, Pyeritz RE, Rubenstein A, Viskochil D
JAMA : the journal of the American Medical Association. 1997 ; 278 (1) : 51-57.
PMID 9207339
New insights into the genetics of familial chromaffin cell tumors.
Koch CA, Vortmeyer AO, Zhuang Z, Brouwers FM, Pacak K
Annals of the New York Academy of Sciences. 2002 ; 970 : 11-28.
PMID 12381538
Selective loss of chromosome 11 in pheochromocytomas associated with the VHL syndrome.
Lui WO, Chen J, Gläsker S, Bender BU, Madura C, Khoo SK, Kort E, Larsson C, Neumann HP, Teh BT
Oncogene. 2002 ; 21 (7) : 1117-1122.
PMID 11850829
The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis.
Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ
Nature. 1999 ; 399 (6733) : 271-275.
PMID 10353251
How many pathways to pheochromocytoma?
Neumann HP, Hoegerle S, Manz T, Brenner K, Iliopoulos O
Seminars in nephrology. 2002 ; 22 (2) : 89-99.
PMID 11891502
Pheochromocytoma in multiple endocrine neoplasia type 2: a prospective study.
Nguyen L, Niccoli-Sire P, Caron P, Bastie D, Maes B, Chabrier G, Chabre O, Rohmer V, Lecomte P, Henry JF, French Calcitonin Tumors Study Group, Conte-Devolx B
European journal of endocrinology / European Federation of Endocrine Societies. 2001 ; 144 (1) : 37-44.
PMID 11174835
Tumor recurrence and hypertension persistence after successful pheochromocytoma operation.
Plouin PF, Chatellier G, Fofol I, Corvol P
Hypertension. 1997 ; 29 (5) : 1133-1139.
PMID 9149678
Factors associated with perioperative morbidity and mortality in patients with pheochromocytoma: analysis of 165 operations at a single center.
Plouin PF, Duclos JM, Soppelsa F, Boublil G, Chatellier G
The Journal of clinical endocrinology and metabolism. 2001 ; 86 (4) : 1480-1486.
PMID 11297571
Familial malignant catecholamine-secreting paraganglioma with prolonged survival associated with mutation in the succinate dehydrogenase B gene.
Young AL, Baysal BE, Deb A, Young WF Jr
The Journal of clinical endocrinology and metabolism. 2002 ; 87 (9) : 4101-4105.
PMID 12213855


This paper should be referenced as such :
Gimenez-Roqueplo, AP
Neuroendocrine tumors: Phaeochromocytoma
Atlas Genet Cytogenet Oncol Haematol. 2003;7(2):125-128.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Other genes implicated (Data extracted from papers in the Atlas) [ 32 ]


External links

arrayMap Topo ( C74) arrayMap ((UZH-SIB Zurich)   [auto + random 100 samples .. if exist ]   [tabulated segments]
Disease databaseNeuro-Endocrine/Endocrine system: Phaeochromocytoma
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