1. bookVolume 52 (2018): Issue 1 (January 2018)
Journal Details
First Published
30 Mar 2016
Publication timeframe
4 times per year
Open Access

Genetic and epigenetic differences of benign and malignant pheochromocytomas and paragangliomas (PPGLs)

Published Online: 16 Feb 2018
Volume & Issue: Volume 52 (2018) - Issue 1 (January 2018)
Page range: 41 - 54
Journal Details
First Published
30 Mar 2016
Publication timeframe
4 times per year

Pheochromocytomas and paragangliomas (PPGLs) are tumors arising from the adrenal medulla and sympathetic/parasympathetic paraganglia, respectively. According to Th e Cancer Genome Atlas (TCGA), approximately 40% of PPGLs are due to germ line mutations in one of 16 susceptibility genes, and a further 30% are due to somatic alterations in at least seven main genes (VHL, EPAS1, CSDE1, MAX, HRAS, NF1, RET, and possibly KIF1B). Th e diagnosis of malignant PPGL was straight forward in most cases as it was defined as presence of PPGL in non-chromaffin tissues. Accordingly, there is an extreme need for new diagnostic marker(s) to identify tumors with malignant prospective. Th e aim of this study was to review all suggested genetic and epigenetic alterations that are remarkably different between benign and malignant PPGLs. It seems that more than two genetic mutation clusters in PPGLs and other genetic and methylation biomarkers could be targeted for malignancy discrimination in different studies.


Agarwal SK, Guru SC, Heppner C, Erdos MR, Collins RM, Park SY, Saggar S, Chandrasekharappa SC, Collins FS, Spiegel AM, Marx SJ, Burns AL. Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription. Cell 96, 143-152, 1999.10.1016/S0092-8674(00)80967-8Search in Google Scholar

Akerstrom G . Introduction to symposium: ‘New genetics with impact on treatment of endocrine tumour disease’. J Intern Med 280, 536-539, 2016.10.1111/joim.12518Search in Google Scholar

Amar L, Bertherat J, Baudin E, Ajzenberg C, Bressac-de Paillerets B, Chabre O, Chamontin B, Delemer B, Giraud S, Murat A, Niccoli-Sire P, Richard S, Rohmer V, Sadoul JL, Strompf L, Schlumberger M, Bertagna X, Plouin PF, Jeunemaitre X, Gimenez-Roqueplo AP. Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol 23, 8812-8818, 2005.10.1200/JCO.2005.03.1484Open DOISearch in Google Scholar

Amar L, Baudin E, Burnichon N, Peyrard S, Silvera S, Bertherat J, Bertagna X, Schlumberger M, Jeunemaitre X, Gimenez-Roqueplo AP, Plouin PF. Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas. J Clin Endocrinol Metab 92, 3822-3828, 2007.10.1210/jc.2007-0709Open DOISearch in Google Scholar

Amousha MRH, Sabetkish N, Heshmat R, Rajabiani A, Saff ar H, Haghpanah V, Tavangar SM. Expression of the pituitary tumor transforming gene (PTTG1) in pheochromocytoma as a potential marker for distinguishing benign versus malignant tumors. Acta Med Iran 53, 236-241, 2015.Search in Google Scholar

Assadipour Y, Sadowski SM, Alimchandani M, Quezado M, Steinberg SM, Nilubol N, Patel D, Prodanov T, Pacak K, Kebebew E. SDHB mutation status and tumor size but not tumor grade are important predictors of clinical outcome in pheochromocytoma and abdominal paraganglioma. Surgery 161, 230-239, 2017.10.1016/j.surg.2016.05.050Search in Google Scholar

Backman S, Crona J, Maharjan R, Stalberg P, Hellman P, Bjorklund P. Global promoter methylation analysis identifi es malignant pheochromocytomas. Meeting Abstracts, Adrenal Tumors, Glucocorticoid Regulation and Action, Endocrine Society’s 97th Annual Meeting and Expo, FRI-358, 2015.Search in Google Scholar

Backman S, Maharjan R, Falk-Delgado A, Crona J, Cupisti K, Stalberg P, Hellman P, Bjorklund P. Global DNA Methylation Analysis Identifi es Two Discrete clusters of Pheochromocytoma with Distinct Genomic and Genetic Alterations. Sci Rep 7, 44943, 2017.10.1038/srep44943Search in Google Scholar

Bayley JP, Kunst HP, Cascon A, Sampietro ML, Gaal J, Korpershoek E, Hinojar-Gutierrez A, Timmers HJ, Hoefsloot LH, Hermsen MA, Suarez C, Hussain AK, Vriends AH, Hes FJ, Jansen JC, Tops CM, Corssmit EP, de Knijff P, Lenders JW, Cremers CW, Devilee P, Dinjens WN, de Krijger RR, Robledo M. SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma. Lancet Oncol 11, 366-372, 2010.10.1016/S1470-2045(10)70007-3Open DOISearch in Google Scholar

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. Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas. J Med Genet 39, 178-183, 2002.10.1136/jmg.39.3.178173506111897817Search in Google Scholar

Boltze C, Mundschenk J, Unger N, Schneider-Stock R, Peters B, Mawrin C, Hoang-Vu C, Roessner A, Lehnert H. Expression profi le of the telomeric complex discriminates between benign and malignant pheochromocytoma. J Clin Endocrinol Metab 88, 4280-4286, 2003.10.1210/jc.2002-02129912970299Open DOISearch in Google Scholar

Boron WF, Boulpaep EL. (Eds.) Medical Physiology: A Cellular and Molecular Approach. Saunders, 2009.Search in Google Scholar

Brouwers FM, Elkahloun AG, Munson PJ, Eisenhofer G, Barb J, Linehan WM, Lenders JW, De Krijger R, Mannelli M, Udelsman R, Ocal IT, Shulkin BL, Bornstein SR, Breza J, Ksinantova L, Pacak K. Gene expression profi ling of benign and malignant pheochromocytoma. Ann N Y Acad Sci 1073, 541-556, 2006.10.1196/annals.1353.058556048517102123Search in Google Scholar

Bryant J, Farmer J, Kessler LJ, Townsend RR, Nathanson KL. Pheochromocytoma: the expanding genetic diff erential diagnosis. J Natl Cancer Inst 95, 1196-1204, 2003.10.1093/jnci/djg02412928344Search in Google Scholar

Burnichon N, Cascon A, Schiavi F, Morales NP, Comino-Mendez I, Abermil N et al. MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma. Clin Cancer Res 18, 2828-2837, 2012.10.1158/1078-0432.CCR-12-016022452945Open DOISearch in Google Scholar

Burnichon N, Buff et A, Gimenez-Roqueplo AP. Pheochromocytoma and paraganglioma: molecular testing and personalized medicine. Curr Opin Oncol 28, 5-10, 2016.10.1097/CCO.000000000000024926599293Open DOISearch in Google Scholar

Capelli P, Martignoni G, Pedica F, Falconi M, Antonello D, Malpeli G, Scarpa A. Endocrine neoplasms of the pancreas: pathologic and genetic features. Arch Pathol Lab Med 133, 350-364, 2009.10.5858/133.3.35019260741Search in Google Scholar

Castro-Vega LJ, Buff et A, De Cubas AA, Cascon A, Menara M, Khalifa E, Amar L, Azriel S, Bourdeau I, Chabre O, Curras-Freixes M, Franco-Vidal V, Guillaud-Bataille M, Simian C, Morin A, Leton R, Gomez-Grana A, Pollard PJ, Rustin P, Robledo M, Favier J, Gimenez-Roqueplo AP. Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas. Hum Mol Genet 23, 2440-2446, 2014.10.1093/hmg/ddt63924334767Open DOISearch in Google Scholar

Chen H, Sippel RS, O’Dorisio MS, Vinik AI, Lloyd RV, Pacak K; North American Neuroendocrine Tumor Society (NANETS). Th e North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer. Pancreas 39, 775-783, 2010.10.1097/MPA.0b013e3181ebb4f0341900720664475Search in Google Scholar

Comino-Mendez I, Gracia-Aznarez FJ, Schiavi F, Landa I, Leandro-Garcia LJ, Leton R, Honrado E, Ramos-Medina R, Caronia D, Pita G, Gomez-Grana A, de Cubas AA, Inglada-Perez L, Maliszewska A, Taschin E, Bobisse S, Pica G, Loli P, Hernandez-Lavado R, Diaz JA, Gomez-Morales M, Gonzalez-Neira A, Roncador G, Rodriguez-Antona C, Benitez J, Mannelli M, Opocher G, Robledo M, Cascon A. Exome sequencing identifi es MAX mutations as a cause of hereditary pheochromocytoma. Nat Genet 43, 663-667, 2011.10.1038/ng.86121685915Open DOISearch in Google Scholar

Cwikla JB, Bodei L, Kolasinska-Cwikla A, Sankowski A, Modlin IM, Kidd M. Circulating transcript analysis (NETest) in GEP-NETs treated with somatostatin analogs defi nes therapy. J Clin Endocrinol Metab 100, E1437-E1445, 2015.10.1210/jc.2015-279226348352Search in Google Scholar

Dahia PL, Ross KN, Wright ME, Hayashida CY, Santagata S, Barontini M, Kung AL, Sanso G, Powers JF, Tischler AS, Hodin R, Heitritter S, Moore F, Dluhy R, Sosa JA, Ocal IT, Benn DE, Marsh DJ, Robinson BG, Schneider K, Garber J, Arum SM, Korbonits M, Grossman A, Pigny P, Toledo SP, Nose V, Li C, Stiles CD. A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genet 1, 72-80, 200 5.10.1371/journal.pgen.0010008118352716103922Search in Google Scholar

Dahia PL. Pheochromocytoma and paraganglioma pathogenesis: learning from genetic heterogeneity. Nat Rev Cancer 14, 108-119, 2014.10.1038/nrc364824442145Open DOISearch in Google Scholar

Darr R, Lenders JW, Hofb auer LC, Naumann B, Bornstein SR, Eisenhofer G. Pheochromocytoma - update on disease management. Th er Adv Endocrinol Metab 3, 11-26, 2012.10.1177/2042018812437356Search in Google Scholar

de Cubas AA, Korpershoek E, Inglada-Perez L, Letouze E, Curras-Freixes M, Fernandez AF, Comino-Mendez I, Schiavi F, Mancikova V, Eisenhofer G, Mannelli M, Opocher G, Timmers H, Beuschlein F, de Krijger R, Cascon A, Rodriguez-Antona C, Fraga MF, Favier J, Gimenez-Roqueplo AP, Robledo M. DNA methylation profiling in pheochromocytoma and paraganglioma reveals diagnostic and prognostic markers. Clin Cancer Res 21, 3020-3030, 2015.10.1158/1078-0432.CCR-14-2804Open DOISearch in Google Scholar

DeLellis RA, Lloyd RV, H eitz PU, Eng C. (Eds.): World Health Organization Classifi cation of Tumours. Pathology and Genetics of Tumours of Endocrine Organs. IARC Press: Lyon 2004.Search in Google Scholar

Eisenhofer G, Kopin IJ, Goldstein DS. Catecholamine metabolism: a contemporary view with implications for physiology and medicine. Pharmacol Rev 56, 331-349, 2004a.10.1124/pr.56.3.1Open DOISearch in Google Scholar

Eisenhofer G, Bornstein SR, Brouwers FM, Cheung NK, Dahia PL, de Krijger RR, Giordano TJ, Greene LA, Goldstein DS, Lehnert H, Manger WM, Maris JM, Neumann HP, Pacak K, Shulkin BL, Smith DI, Tischler AS, Young WF Jr. Malignant pheochromocytoma: current status and initiatives for future progress. Endocr Relat Cancer 11, 423-436, 2004b.10.1677/erc.1.00829Open DOISearch in Google Scholar

Elder EE, Xu D, Hoog A, Enberg U, Hou M, Pisa P, Gruber A, Larsson C, Backdahl M. KI-67 AND hTERT expression can aid in the distinction between malignant and benign pheochromocytoma and paraganglioma. Mod Pathol 16, 246-255, 2003.10.1097/01.MP.0000056982.07160.E3Search in Google Scholar

Favier J, Plouin PF, Cor vol P, Gasc JM. Angiogenesis and vascular architecture in pheochromocytomas: distinctive traits in malignant tumors. Am J Pathol 161, 1235-1246, 2002.10.1016/S0002-9440(10)64400-8Search in Google Scholar

Favier J, Gimenez-Roquep lo AP. Pheochromocytomas: the (pseudo)-hypoxia hypothesis. Best Pract Res Clin Endocrinol Metab 24, 957-968, 2010.10.1016/j.beem.2010.10.00421115164Open DOISearch in Google Scholar

Favier J, Gimenez-Roquep lo AP. [Genetics of paragangliomas and pheochromocytomas]. Med Sci (Paris) 28, 625- 632, 2012.10.1051/medsci/201228601622805139Search in Google Scholar

Favier J, Amar L, Gimene z-Roqueplo AP. Paraganglioma and phaeochromocytoma: from genetics to personalized medicine. Nat Rev Endocrinol 11, 101-111, 2015.10.1038/nrendo.2014.18825385035Open DOISearch in Google Scholar

Fishbein L, Merrill S, F raker DL, Cohen DL, Nathanson KL. Inherited mutations in pheochromocytoma and paraganglioma: why all patients should be off ered genetic testing. Ann Surg Oncol 20, 1444-1450, 2013.10.1245/s10434-013-2942-5429128123512077Open DOISearch in Google Scholar

Fishbein L, Khare S, Wubbenhorst B, DeSloover D, D’Andrea K, Merrill S, Cho NW, Greenberg RA, Else T, Montone K, LiVolsi V, Fraker D, Daber R, Cohen DL, Nathanson KL. Whole-exome sequencing identifi es somatic ATRX mutations in pheochromocytomas and paragangliomas. Nat Commun 6, 6140, 2015.10.1038/ncomms7140430275725608029Search in Google Scholar

Fishbein L. Pheochromocy toma and paraganglioma: genetics, diagnosis, and treatment. Hematol Oncol Clin North Am 30, 135-150, 2016.10.1016/j.hoc.2015.09.00626614373Open DOISearch in Google Scholar

Fishbein L, Leshchiner I, Walter V, Danilova L, Robertson AG, Johnson A et al. Abstract 4371: Integrated molecular characterization of pheochromocytoma and paraganglioma including a novel, recurrent and prognostic fusion gene. Cancer Research 76, 4371, 2016.10.1158/1538-7445.AM2016-4371Open DOISearch in Google Scholar

Fishbein L, Leshchiner I , Walter V, Danilova L, Robertson AG, Johnson AR et al. Comprehensive molecular characterization of pheochromocytoma and paraganglioma. Cancer Cell 31, 181-193, 2017.10.1016/j.ccell.2017.01.001564315928162975Open DOISearch in Google Scholar

Galan SR, Kann PH. Genet ics and molecular pathogenesis of pheochromocytoma and paraganglioma. Clin Endocrinol (Oxf) 78, 165-175, 2013.10.1111/cen.1207123061808Open DOISearch in Google Scholar

Geli J, Kiss N, Lanner F , Foukakis T, Natalishvili N, Larsson O, Kogner P, Hoog A, Clark GJ, Ekstrom TJ, Backdahl M, Farnebo F, Larsson C. Th e Ras eff ectors NORE1A and RASSF1A are frequently inactivated in pheochromocytoma and abdominal paraganglioma. Endocr Relat Cancer 14, 125-134, 2007.10.1677/ERC-06-003117395981Open DOISearch in Google Scholar

Gimenez-Roqueplo AP. Gen etics of paragangliomas and pheochromocytoma. Abstracts for the Ninth International Workshop on Multiple Endocrine Neoplasia (MEN2004) Journal of Internal Medicine 255, 703, 2004.10.1111/j.1365-2796.2004.01343.xSearch in Google Scholar

Gimenez-Roqueplo AP, Dah ia PL, Robledo M. An update on the genetics of paraganglioma, pheochromocytoma, and associated hereditary syndromes. Horm Metab Res 44, 328-333, 2012.10.1055/s-0031-130130222328163Search in Google Scholar

Giubellino A, Sourbier C , Lee MJ, Scroggins B, Bullova P, Landau M, Ying W, Neckers L, Trepel JB, Pacak K. Targeting heat shock protein 90 for the treatment of malignant pheochromocytoma. PLoS One 8, e56083, 2013.10.1371/journal.pone.0056083357306623457505Search in Google Scholar

Guo Z, Lloyd RV. Pheochr omocytomas and paragangliomas: an update on recent molecular genetic advances and criteria for malignancy. Adv Anat Pathol 22, 283-293, 2015.10.1097/PAP.000000000000008626262510Open DOISearch in Google Scholar

Haghpanah V, Shooshtariz adeh P, Heshmat R, Larijani B, Tavangar SM. Immunohistochemical analysis of survivin expression in thyroid follicular adenoma and carcinoma. Appl Immunohistochem Mol Morphol 14, 422-425, 2006.10.1097/01.pai.0000213100.88074.b817122639Open DOISearch in Google Scholar

Hasani-Ranjbar S1, Amoli MM, Ebrahim-Habibi A, Haghpanah V, Hejazi M, Soltani A, Larijani B. Mutation screening of VHL gene in a family with malignant bilateral pheochromocytoma: from isolated familial pheochromocytoma to von Hippel-Lindau disease. Fam Cancer 8, 465-471, 2009.10.1007/s10689-009-9266-419649731Search in Google Scholar

Hasani-Ranjbar S, Amoli MM, Ebrahim-Habibi A, Gozashti MH, Khalili N, Sayyahpour FA, Hafeziyeh J, Soltani A, Larijani B. A new frameshift MEN1 gene mutation associated with familial malignant insulinomas. Fam Cancer 10, 343-348, 2011.10.1007/s10689-010-9412-z21184284Search in Google Scholar

Helman LJ, Cohen PS, Averbuch SD, Cooper MJ, Keiser HR, Israel MA. Neuropeptide Y expression distinguishes malignant from benign pheochromocytoma. J Clin Oncol 7, 1720-1725, 1989.10.1200/JCO.1989.7.11.17202809684Open DOISearch in Google Scholar

Jones PA. DNA methylatio n and cancer. Cancer Res 46, 461-466, 1986.Search in Google Scholar

Juhlin CC, Stenman A, Ha glund F, Clark VE, Brown TC, Baranoski J, Bilguvar K, Goh G, Welander J, Svahn F, Rubinstein JC, Caramuta S, Yasuno K, Gunel M, Backdahl M, Gimm O, Soderkvist P, Prasad ML, Korah R, Lift on RP, Carling T. Whole‐exome sequencing defi nes the mutational landscape of pheochromocytoma and identifi es KMT2D as a recurrently mutated gene. Genes Chromosomes Cancer 54, 542-554, 2015.10.1002/gcc.22267475514226032282Search in Google Scholar

Kajbafzadeh AM, Payabvash S, Salmasi AH, Monajemzadeh M, Tavangar SM. Smooth muscle cell apoptosis and defective neural development in congenital ureteropelvic junction obstruction. J Urol 176, 718-723, 2006.10.1016/j.juro.2006.03.04116813927Search in Google Scholar

Khatami F, Noorinayer B, Ghiasi S, Mohebi R, Hashemi M, Zali MR. Lack of eff ects of single nucleotide polymorphisms of the DNA methyltransferase 1 gene on gastric cancer in Iranian patients: a case control study. Asian Pac J Cancer Prev 10, 1177-1182, 2009a.Search in Google Scholar

Khatami F, Noorinayer B, Mohebi SR, Ghiasi S, Mohebi R, Hashemi M, Zali MR. Eff ects of amino acid substitution polymorphisms of two DNA methyltransferases on susceptibility to sporadic colorectal cancer. Asian Pac J Cancer Prev 10, 1183-1188, 2009b.Search in Google Scholar

Khatami F, Tavangar SM. Current diagnostic status of pheochromocytoma and future perspective: A mini review. Iran J Pathol 12, 313-322, 2017.10.30699/ijp.2017.26267Search in Google Scholar

Khatami F, Larijani B, Ta vangar SM Circulating tumor BRAF mutation and personalized thyroid cancer treatment. Asian Pac J Cancer Prev 18, 293-294, 2017a.Search in Google Scholar

Khatami F, Aghayan HR, Sanaei M, Heshmat R, Tavangar SM, Larijani B. Th e potential of circulating tumor cells in personalized management of breast cancer: A systematic review. Acta Med Iran 55, 175-193, 2017b.Search in Google Scholar

Kidd M, Drozdov I, Modlin I. Blood and tissue neuroendocrine tumor gene cluster analysis correlate, defi ne hallmarks and predict disease status. Endocr Relat Cancer 22, 561-575, 2015.10.1530/ERC-15-009226037279Open DOISearch in Google Scholar

Kimura N, Takayanagi R, T akizawa N, Itagaki E, Katabami T, Kakoi N, Rakugi H, Ikeda Y, Tanabe A, Nigawara T, Ito S, Kimura I, Naruse M; Phaeochromocytoma Study Group in Japan. Pathological grading for predicting metastasis in phaeochromocytoma and paraganglioma. Endocr Relat Cancer 21, 405-414, 2014.10.1530/ERC-13-049424521857Open DOISearch in Google Scholar

Kleihues P, Louis DN, Sch eithauer BW, Rorke LB, Reifenberger G, Burger PC, Cavenee WK. Th e WHO classifi cation of tumors of the nervous system. J Neuropathol Exp Neurol 61, 215-229, 2002.10.1093/jnen/61.3.21511895036Search in Google Scholar

Kouros-Mehr H, Slorach EM , Sternlicht MD, Werb Z. GATA-3 maintains the diff erentiation of the luminal cell fate in the mammary gland. Cell 127, 1041-1055, 2006.10.1016/j.cell.2006.09.048Search in Google Scholar

Larijani B, Shirzad M, Mo hagheghi MA, Haghpanah V, Mosavi-Jarrahi AR, Tavangar SM, Vassigh AR, Hossein-Nezhad A, Bandarian F, Baradar-Jalili R. Epidemiologic analysis of the Tehran cancer institute data system registry (TCIDSR). Asian Pac J Cancer Prev 5, 36-39, 2004.Search in Google Scholar

Lee S, Nakamura E, Yang H , Wei W, Linggi MS, Sajan MP, Farese RV, Freeman RS, Carter BD, Kaelin WG Jr, Schlisio S. Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer. Cancer Cell 8, 155-167, 2005.10.1016/j.ccr.2005.06.015Search in Google Scholar

Letouze E, Martinelli C, Loriot C, Burnichon N, Abermil N, Ottolenghi C, Janin M, Menara M, Nguyen AT, Benit P, Buff et A, Marcaillou C, Bertherat J, Amar L, Rustin P, De Reynies A, Gimenez-Roqueplo AP, Favier J. SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell 23, 739-752, 2013.10.1016/j.ccr.2013.04.018Open DOISearch in Google Scholar

Li SC, Essaghir A, Martij n C, Lloyd RV, Demoulin JB, Oberg K, Giandomenico V. Global microRNA profi ling of well-diff erentiated small intestinal neuroendocrine tumors. Mod Pathol 26, 685-696, 2013.10.1038/modpathol.2012.216Search in Google Scholar

Linnoila RI, Keiser HR, S teinberg SM, Lack EE. Histopathology of benign versus malignant sympathoadrenal paragangliomas: clinicopathologic study of 120 cases including unusual histologic features. Hum Pathol 21, 1168-1180, 1990.10.1016/0046-8177(90)90155-XSearch in Google Scholar

Lopez-Jimenez E, Gomez-Lo pez G, Leandro-Garcia LJ, Munoz I, Schiavi F, Montero-Conde C, de Cubas AA, Ramires R, Landa I, Leskela S, Maliszewska A, Inglada-Perez L, de la Vega L, Rodriguez-Antona C, Leton R, Bernal C, de Campos JM, Diez-Tascon C, Fraga MF, Boullosa C, Pisano DG, Opocher G, Robledo M, Cascon A. Research resource: transcriptional profi ling reveals diff erent pseudohypoxic signatures in SDHB and VHLrelated pheochromocytomas. Mol Endocrinol 24, 2382-2391, 2010.10.1210/me.2010-0256541737220980436Open DOISearch in Google Scholar

Majidi M, Haghpanah V, He dayati M, Khashayar P, Mohajeri-Tehrani MR, Larijani B. A family presenting with multiple endocrine neoplasia type 2B: A case report. J Med Case Rep 5, 587, 2011.10.1186/1752-1947-5-587328741122185228Search in Google Scholar

Mannelli M, Castellano M, Schiavi F, Filetti S, Giacche M, Mori L, Pignataro V, Bernini G, Giache V, Bacca A, Biondi B, Corona G, Di Trapani G, Grossrubatscher E, Reimondo G, Arnaldi G, Giacchetti G, Veglio F, Loli P, Colao A, Ambrosio MR, Terzolo M, Letizia C, Ercolino T, Opocher G; Italian heochromocytoma/Paraganglioma Network. Clinically guided genetic screening in a large cohort of italian patients with pheochromocytomas and/or functional or nonfunctional paragangliomas. J Clin Endocrinol Metab 94, 1541-1547, 2009.10.1210/jc.2008-241919223516Open DOISearch in Google Scholar

Margetts CD, Morris M, As tuti D, Gentle DC, Cascon A, McRonald FE, Catchpoole D, Robledo M, Neumann HP, Latif F, Maher ER. Evaluation of a functional epigenetic approach to identify promoter region methylation in phaeochromocytoma and neuroblastoma. Endocr Relat Cancer 15, 777-786, 2008.10.1677/ERC-08-0072251916518499731Open DOISearch in Google Scholar

McNeil AR, Blok BH, Koelm eyer TD, Burke MP, Hilton JM. Phaeochromocytomas discovered during coronial autopsies in Sydney, Melbourne and Auckland. Aust N Z J Med 30, 648-652, 2000.10.1111/j.1445-5994.2000.tb04358.x11198571Search in Google Scholar

Modlin IM, Frilling A, Sa lem RR, Alaimo D, Drymousis P, Wasan HS, Callahan S, Faiz O, Weng L, Teixeira N, Bodei L, Drozdov I, Kidd M. Blood measurement of neuroendocrine gene transcripts defi nes the eff ectiveness of operative resection and ablation strategies. Surgery 159, 336-347, 2016.10.1016/j.surg.2015.06.05626456125Search in Google Scholar

Mohammadi-asl J, Larijani B, Khorgami Z, Tavangar SM, Haghpanah V, Kheirollahi M, Mehdipour P. Qualitative and quantitative promoter hypermethylation patterns of the P16, TSHR, RASSF1A and RARβ2 genes in papillary thyroid carcinoma. Med Oncol 28, 1123-1128, 2011.10.1007/s12032-010-9587-z20535589Open DOISearch in Google Scholar

Mulukutla SN, Rednam SP, Pl on SE, Balazs AE. SUN-005: Th e role of genetics in pheochromocytoma/paraganglioma. Pediatrics-Case Reports II (posters). Endocrine Society’s 98th Annual Meeting and Expo, April 1-4, 2016, Boston.10.1093/edrv/37.supp.1Search in Google Scholar

Muscarella P, Bloomston M, Brewer AR, Mahajan A, Frankel WL, Ellison EC, Farrar WB, Weghorst CM, Li J. Expression of the p16INK4A/Cdkn2a gene is prevalently downregulated in human pheochromocytoma tumor specimens. Gene Expr 14, 207-216, 2008.10.3727/105221608786883825604200119110720Search in Google Scholar

Nasseri-Moghaddam S, Malekz adeh R, Sotoudeh M, Tavangar M, Azimi K, Sohrabpour AA, Mostadjabi P, Fathi H, Minapoor M. Lower esophagus in dyspeptic Iranian patients: a prospective study. J Gastroenterol Hepatol 18, 315-321, 2003.10.1046/j.1440-1746.2003.02969.x12603533Search in Google Scholar

Neumann HP, Bausch B, McWhi nney SR, Bender BU, Gimm O, Franke G, Schipper J, Klisch J, Altehoefer C, Zerres K, Januszewicz A, Eng C, Smith WM, Munk R, Manz T, Glaesker S, Apel TW, Treier M, Reineke M, Walz MK, Hoang-Vu C, Brauckhoff M, Klein-Franke A, Klose P, Schmidt H, Maier-Woelfl e M, Peczkowska M, Szmigielski C, Eng C; Freiburg-Warsaw-Columbus Pheochromocytoma Study Group. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 346, 1459-1466, 2002.10.1056/NEJMoa02015212000816Search in Google Scholar

Nolting S, Grossman AB. Sign aling pathways in pheochromocytomas and paragangliomas: prospects for future therapies. Endocr Pathol 23, 21-33, 2012.10.1007/s12022-012-9199-622391976Open DOISearch in Google Scholar

Ohta S, Lai EW, Pang AL, Bro uwers FM, Chan WY, Eisenhofer G, de Krijger R, Ksinantova L, Breza J, Blazicek P, Kvetnansky R, Wesley RA, Pacak K. Downregulation of metastasis suppressor genes in malignant pheochromocytoma. Int J Cancer 114, 139-143, 2005.10.1002/ijc.2067015523699Search in Google Scholar

Oishi T, Iino K, Okawa Y, Ka kizawa K, Matsunari S, Yamashita M, Taniguchi T, Maekawa M, Suda T, Oki Y. DNA methylation analysis in malignant pheochromocytoma and paraganglioma. J Clin Transl Endocrinol 7, 12- 20, 201610.1016/j.jcte.2016.12.004565129929067245Search in Google Scholar

Palmada M, Kanwal S, Rutkosk i NJ, Gustafson-Brown C, Johnson RS, Wisdom R, Carter BD. c-jun is essential for sympathetic neuronal death induced by NGF withdrawal but not by p75 activation. J Cell Biol 158, 453-461, 2002.10.1083/jcb.200112129217382312163468Search in Google Scholar

Peczkowska M, Cwikla J, Kidd M, Lewczuk A, Kolasinska-Cwikla A, Niec D, Michalowska I, Prejbisz A, Januszewicz A, Chiarelli J, Bodei L, Modlin I. Th e clinical utility of circulating neuroendocrine gene transcript analysis in well-diff erentiated paragangliomas and pheochromocytomas. Eur J Endocrinol 176, 143-157, 2017.10.1530/EJE-16-072727913608Search in Google Scholar

Pavel M, Jann H, Prasad V, Drozdov I, Modlin IM, Kidd M. NET blood transcript analysis defi nes the crossing of the clinical rubicon: When stable disease becomes progressive. Neuroendocrinology 104, 170-182, 2017.10.1159/00044602527078712Search in Google Scholar

Perrino CM, Ho A, Dall CP, Z ynger DL. Utility of GATA3 in the diff erential diagnosis of pheochromocytoma. Histopathology 71, 475-479, 2017.10.1111/his.1322928374498Search in Google Scholar

Pillai S, Gopalan V, Smith R A, Lam AK. Updates on the genetics and the clinical impacts on phaeochromocytoma and paraganglioma in the new era. Crit Rev Oncol Hematol 100, 190-208, 2016.10.1016/j.critrevonc.2016.01.02226839173Open DOISearch in Google Scholar

Rao D, Peitzsch M, Prejbisz A, Hanus K, Fassnacht M, Beuschlein F, Brugger C, Fliedner S, Langton K, Pamporaki C, Gudziol V, Stell A, Januszewicz A, Timmers HJLM, Lenders JWM, Eisenhofer G. Plasma methoxytyramine: clinical utility with metanephrines for diagnosis of pheochromocytoma and paraganglioma. Eur J Endocrinol 177, 103-113, 2017.10.1530/EJE-17-0077548839328476870Search in Google Scholar

Saffar H, Sanii S, Heshmat R , Haghpanah V, Larijani B, Rajabiani A, Azimi S, Tavangar SM. Expression of galectin-3, nm-23, and cyclooxygenase-2 could potentially discriminate between benign and malignant pheochromocytoma. Am J Clin Pathol 135, 454-460, 2011.10.1309/AJCPI8AJLUZ3CZLN21350102Search in Google Scholar

Salajegheh A, Smith RA, Kase m K, Gopalan V, Nassiri MR, William R, Lam AK. Single nucleotide polymorphisms and mRNA expression of VEGF-A in papillary thyroid carcinoma: potential markers for aggressive phenotypes. Eur J Surg Oncol 37, 93-99, 2011.10.1016/j.ejso.2010.10.01021093207Search in Google Scholar

Salajegheh A, Pakneshan S, Rahman A, Dolan-Evans E, Zhang S, Kwong E, Gopalan V, Lo CY, Smith RA, Lam AK. Co-regulatory potential of vascular endothelial growth factor-A and vascular endothelial growth factor-C in thyroid carcinoma. Hum Pathol 44, 2204-2212, 2013.10.1016/j.humpath.2013.04.01423845470Open DOISearch in Google Scholar

Salmenkivi K, Haglund C, Ris timaki A, Arola J, Heikkila P. Increased expression of cyclooxygenase-2 in malignant pheochromocytomas. J Clin Endocrinol Metab 86, 5615-5619, 2001.10.1210/jcem.86.11.805211701743Open DOISearch in Google Scholar

Salmenkivi K, Heikkila P, Li u J, Haglund C, Arola J. VEGF in 105 pheochromocytomas: enhanced expression correlates with malignant outcome. AMPIS 111, 458-464, 2003.10.1034/j.1600-0463.2003.1110402.x12780519Search in Google Scholar

Salmenkivi K, Heikkila P, Haglund C, Arola J. Malignancy in pheochromocytomas. AMPIS 112, 551-559, 2004.10.1111/j.1600-0463.2004.apm1120901.xSearch in Google Scholar

Sandgren J, Andersson R, Rad a-Iglesias A, Enroth S, Akerstrom G, Dumanski JP, Komorowski J, Westin G, Wadelius C. Integrative epigenomic and genomic analysis of malignant pheochromocytoma. Exp Mol Med 42, 484-502, 2010.10.3858/emm.2010.42.7.050Open DOISearch in Google Scholar

Sanii S, Saffar H, Tabriz HM , Qorbani M, Haghpanah V, Tavangar SM. Expression of matrix metalloproteinase-2, but not caspase-3, facilitates distinction between benign and malignant thyroid follicular neoplasms. Asian Pac J Cancer Prev 13, 2175-2178, 2012.10.7314/APJCP.2012.13.5.2175Search in Google Scholar

Sarmadi S, Izadi-Mood N, Sot oudeh K, Tavangar SM. Altered PTEN expression; a diagnostic marker for diff erentiating normal, hyperplastic and neoplastic endometrium. Diagn Pathol 4, 41, 2009.10.1186/1746-1596-4-41Search in Google Scholar

Scholz T, Schulz C, Klose S, Lehnert H. Diagnostic management of benign and malignant pheochromocytoma. Exp Clin Endocrinol Diabetes 115, 155-159, 2007.10.1055/s-2007-970410Search in Google Scholar

Shuch B, Ricketts CJ, Metwal li AR, Pacak K, Linehan WM. Th e genetic basis of pheochromocytoma and paraganglioma: implications for management. Urology 83, 1225-1232, 2014.10.1016/j.urology.2014.01.007Open DOISearch in Google Scholar

Stenstrom G, Svardsudd K. Ph eochromocytoma in Sweden 1958-1981. An analysis of the National Cancer Registry Data. Acta Med Scand 220, 225-232, 1986.10.1111/j.0954-6820.1986.tb02755.xSearch in Google Scholar

Strong VE, Kennedy T, Al-Ahm adie H, Tang L, Coleman J, Fong Y, Brennan M, Ghossein RA. Prognostic indicators of malignancy in adrenal pheochromocytomas: clinical, histopathologic, and cell cycle/apoptosis gene expression analysis. Surgery 143, 759-768, 2008.10.1016/j.surg.2008.02.007Search in Google Scholar

Tabriz HM, Adabi Kh, Lashkar i A, Heshmat R, Haghpanah V, Larijani B, Tavangar SM. Immunohistochemical analysis of nm23 protein expression in thyroid papillary carcinoma and follicular neoplasm. Pathol Res Pract 205, 83-87, 2009.10.1016/j.prp.2008.08.007Search in Google Scholar

Tavangar SM, Larijani B, Mah ta A, Hosseini SM, Mehrazine M, Bandarian F. Craniopharyngioma: a clinicopathological study of 141 cases. Endocr Pathol 15, 339-344, 2004.10.1385/EP:15:4:339Open DOISearch in Google Scholar

Tavangar SM, Sharift abrizi A , Soroush AR. Her-2/neu over-expression correlates with more advanced disease in Iranian colorectal cancer patients. Med Sci Monit 11, CR123-CR126, 2005.Search in Google Scholar

Tavangar SM, Monajemzadeh M, Larijani B, Haghpanah V. Immunohistochemical study of oestrogen receptors in 351 human thyroid glands. Singapore Med J 48, 744-747, 2007.Search in Google Scholar

Tavangar SM, Shojaee A, Moradi Tabriz H, Haghpanah V, Larijani B, Heshmat R, Lashkari A, Azimi S. Immunohistochemical expression of Ki67, c-erbB-2, and c-kit antigens in benign and malignant pheochromocytoma. Pathol Res Pract 206, 305-309, 2010.10.1016/j.prp.2010.01.007Search in Google Scholar

Thompson LD. Pheochromocytom a 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, 2002.10.1097/00000478-200205000-00002Open DOISearch in Google Scholar

Thouennon E, Elkahloun AG, G uillemot J, Gimenez-Roqueplo AP, Bertherat J, Pierre A, Ghzili H, Grumolato L, Muresan M, Klein M, Lefebvre H, Ouafi k L, Vaudry H, Plouin PF, Yon L, Anouar Y. Identifi cation of potential gene markers and insights into the pathophysiology of pheochromocytoma malignancy. J Clin Endocrinol Metab 92, 4865-4872, 2007.10.1210/jc.2007-1253Open DOISearch in Google Scholar

van der Harst E, Bruining HA , Jaap Bonjer H, van der Ham F, Dinjens WN, Lamberts SW, de Herder WW, Koper JW, Stijnen T, Proye C, Lecomte-Houcke M, Bosman FT, de Krijger RR. Proliferative index in phaeochromocytomas: does it predict the occurrence of metastases? J Pathol 191, 175-180, 2000.10.1002/(SICI)1096-9896(200006)191:2<175::AID-PATH615>3.0.CO;2-ZSearch in Google Scholar

Vaque JP, Fernandez-Garcia B , Garcia-Sanz P, Ferrandiz N, Bretones G, Calvo F, Crespo P, Marin MC, Leon J. c-Myc inhibits Ras-mediated diff erentiation of pheochromocytoma cells by blocking c-Jun up-regulation. Mol Cancer Res 6, 325-339, 2008.10.1158/1541-7786.MCR-07-0180Open DOISearch in Google Scholar

Vogel KS, Brannan CI, Jenkin s NA, Copeland NG, Parada LF. Loss of neurofi bromin results in neurotrophin-independent survival of embryonic sensory and sympathetic neurons. Cell 82, 733-742, 1995.10.1016/0092-8674(95)90470-0Open DOISearch in Google Scholar

Welander J, Andreasson A, Br auckhoff M, Backdahl M, Larsson C, Gimm O, Soderkvist P. Frequent EPAS1/HIF2α exons 9 and 12 mutations in non-familial pheochromocytoma. Endocr Relat Cancer 21, 495-504, 2014.10.1530/ERC-13-0384Search in Google Scholar

Walenkamp A, Crespo G, Fierro Maya F, Fossmark R, Igaz P, Rinke A, Tamagno G, Vitale G, Oberg K, Meyer T. Hallmarks of gastrointestinal neuroendocrine tumours: implications for treatment. Endocr Relat Cancer 21, R445-R460, 2014.10.1530/ERC-14-0106Open DOISearch in Google Scholar

Wilzen A, Rehammar A, Muth A, N ilsson O, Tesan Tomic T, Wangberg B, Kristiansson E, Abel F. Malignant pheochromocytomas/paragangliomas harbor mutations in transport and cell adhesion genes. Int J Cancer 138, 2201-2211, 2016.10.1002/ijc.29957Search in Google Scholar

Yalcin S, Oberg K (Eds). Neuroe ndocrine Tumours. Diagnosis and Management. Springer-Verlag Berlin Heidelberg, 2015. Search in Google Scholar

Yang C, Zhuang Z, Fliedner SM, Shankavaram U, Sun MG, Bullova P, Zhu R, Elkahloun AG, Kourlas PJ, Merino M, Kebebew E, Pacak K. Germ-line PHD1 and PHD2 mutations detected in patients with pheochromocytoma/paraganglioma-polycythemia. J Mol Med (Berl) 93, 93-104, 2015.10.1007/s00109-014-1205-7Search in Google Scholar

Yon L, Guillemot J, Montero-Hadjadje M, Grumolato L, Leprince J, Lefebvre H, Contesse V, Plouin PF, Vaudry H, Anouar Y. Identifi cation of the secretogranin II-derived peptide EM66 in pheochromocytomas as a potential marker for discriminating benign versus malignant tumors. J Clin Endocrinol Metab 88, 2579-2585, 2003.10.1210/jc.2002-02174812788858Open DOISearch in Google Scholar

Yu R, Nissen NN, Chopra P, Dhall D, Phillips E, Wei M. Diagnosis and treatment of pheochromocytoma in an acade mic hospital from 1997 to 2007. Am J Med 122, 85-95, 2009.10.1016/j.amjmed.2008.08.02119114176Search in Google Scholar

Yuan W, Wang W, Cui B, Su T, Ge Y, Jiang L, Zhou W, Ning G. Overexpression of ERBB-2 was more frequently detec ted in malignant than benign pheochromocytomas by multiplex ligation-dependent probe amplifi cation and immunohistochemistry. Endocr Relat Cancer 15, 343-350, 2008.10.1677/ERC-07-0188225451118310300Open DOISearch in Google Scholar

Zhikrivetskaya SO, Snezhkina AV, Zaretsky AR, Alekseev BY, Pokrovsky AV, Golovyuk AL, Melnikova NV, Stepanov O A, Kalinin DV, Moskalev AA, Krasnov GS, Dmitriev AA, Kudryavtseva AV. Molecular markers of paragangliomas/pheochromocytomas. Oncotarget 8, 25756-25782, 2017.10.18632/oncotarget.15201542196728187001Search in Google Scholar

Recommended articles from Trend MD

Plan your remote conference with Sciendo