Genetics and the Clinical Approach to Paragangliomas

K.-M. Schulte; N. Talat; G. Galata; S. Aylwin; L. Izatt; G. Eisenhofer; A. Barthel; S. R. Bornstein

doi:10.1055/s-0034-1383581

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2014; 46(13): 964-973
DOI: 10.1055/s-0034-1383581

Endocrine Care

Genetics and the Clinical Approach to Paragangliomas

K.-M. Schulte

¹Department of Endocrine Surgery, King’s College Hospital, King’s Health Partners, London, UK

²Department of Surgery, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia

,

N. Talat

¹Department of Endocrine Surgery, King’s College Hospital, King’s Health Partners, London, UK

,

G. Galata

¹Department of Endocrine Surgery, King’s College Hospital, King’s Health Partners, London, UK

,

S. Aylwin

³Department of Endocrinology, King’s College Hospital, King’s Health Partners, London, UK

,

L. Izatt

⁴Clinical Genetics Department, Guy’s Hospital, London, UK

,

G. Eisenhofer

⁵Institute of Clinical Chemistry and Laboratory Medicine, University Hospital of Dresden, Dresden, Germany

⁶Department of Medicine III, University Hospital of Dresden, Dresden, Germany

,

A. Barthel

⁶Department of Medicine III, University Hospital of Dresden, Dresden, Germany

⁷Endokrinologikum RUHR, Bochum, Germany

,

S. R. Bornstein

⁶Department of Medicine III, University Hospital of Dresden, Dresden, Germany

⁸Department of Diabetes and Endocrinology, King’s College London, London, UK

› Author Affiliations

Abstract

This study analyses new information on gene mutations in paragangliomas and puts them into a clinical context. A suspicion of malignancy is critical to determine the workup and surgical approach in adrenal (A-PGL) and extra-adrenal (E-PGL) paragangliomas (PGLs). Malignancy rates vary with location, family history, and gene tests results. Currently there is no algorithm incorporating the above information for clinical use. A sum of 1 821 articles were retrieved from PubMed using the search terms “paraganglioma genetics”. Thirty-seven articles were selected of which 9 were analyzed. It was found that 599/2 487 (24%) patients affected with paragangliomas had a germline mutation. Of these 30.2% were mutations in SDHB, 25% VHL, 19.4% RET, 18.4% SDHD, 5.0% NF1, and 2.0% SDHC genes. A family history was positive in 18.1–64.3% of patients. Adrenal PGLs accounted for 55.1% in mutation (+) and 81.0% in mutation (−) patients (RR 1.2, p<0.0001). Bilateral A-PGLs accounted for 56.4% in mutation (+) and 3.2% in mutation (−) patients (RR 8.7, p<0.0001). E-PGL were found in 33.6% of mut+ and 17.3% of mut– (RR 1.7, p<0.0001). In mutation (+) patients PGLs malignancy varied with location, adrenal (6.4%) thoraco-abdominal E-PGL (38%), H & N E-PGL (10%). Malignancy rates were 8.2% in mutation (−) and lower in mutation (+) PGLs except for SDHB 36.5% and SDHC 8.3%. Exclusion of a mutation lowered the probability of malignancy significantly in E-PGL (RR 0.03 (95% CI 0.1–0.6); p<0.001). Mutation analysis provides valuable preoperative information to assess the risk of malignancy in A-PG and E-PGLs and should be considered in the work up of all E-PGL lesions.

Key words

paraganglioma - cancer - malignancy - germline mutations

Full Text

References

References
1 Galan SR, Kann PH. Genetics and molecular pathogenesis of pheochromocytoma and paraganglioma. Clin Endocrinol (Oxf) 2013; 78: 165-175
2 Welander J, Soderkvist P, Gimm O. Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas. Endocr Relat Cancer 2011; 18: R253-R276
3 Jafri M, Maher ER. The genetics of phaeochromocytoma: using clinical features to guide genetic testing. Eur J Endocrinol 2012; 166: 151-158
4 Koch CA, Pacak K, Chrousos GP. The molecular pathogenesis of hereditary and sporadic adrenocortical and adrenomedullary tumors. J Clin Endocrinol Metab 2002; 87: 5367-5384
5 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. Clinically guided genetic screening in a large cohort of Italian patients with pheochromocytomas and/or functional or nonfunctional paragangliomas. J Clin Endocrinol Metab 2009; 94: 1541-1547
6 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 J-L, Strompf L, Schlumberger M, Bertagna X, Plouin P-F, Jeunemaitre X, Gimenez-Roqueplo A-P. Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol 2005; 23: 8812-8818
7 Erlic Z, Rybicki L, Peczkowska M, Golcher H, Kann PH, Brauckhoff M, Müssig K, Muresan M, Schäffler A, Reisch N, Schott M, Fassnacht M, Opocher G, Klose S, Fottner C, Forrer F, Plöckinger U, Petersenn S, Zabolotny D, Kollukch O, Yaremchuk S, Januszewicz A, Walz MK, Eng C, Neumann H PH. and for the European-American Pheochromocytoma Study Group . Clinical predictors and algorithm for the genetic diagnosis of pheochromocytoma patients. Clin Cancer Res 2009; 15: 6378-6385
8 Neumann HP, Bausch B, McWhinney 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-Woelfle M, Peczkowska M, Szmigielski C, Eng C. Freiburg-Warsaw-Columbus Pheochromocytoma Study Group . Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 2002; 346: 1459-1466
9 Venkatesan AM, Trivedi H, Adams KT, Kebebew E, Pacak K, Hughes MB. Comparison of clinical and imaging features in succinate dehydrogenase-positive versus sporadic paragangliomas. Surgery 2011; 150: 1186-1193
10 Brouwers FM, Eisenhofer G, Tao JJ, Kant JA, Adams KT, Linehan WM, Pacak K. High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing. J Clin Endocrinol Metab 2006; 91: 4505-4509
11 King KS, Prodanov T, Kantorovich V, Fojo T, Hewitt JK, Zacharin M, Wesley R, Lodish M, Raygada M, Gimenez-Roqueplo AP, McCormack S, Eisenhofer G, Milosevic D, Kebebew E, Stratakis CA, Pacak K. Metastatic pheochromocytoma/paraganglioma related to primary tumor development in childhood or adolescence: significant link to SDHB mutations. J Clin Oncol 2011; 29: 4137-4142
12 Burnichon N, Cascon A, Schiavi F, Morales NP, Comino-Mendez I, Abermil N, Inglada-Pérez L, de Cubas AA, Amar L, Barontini M, Bernaldo de Quirós S, Bertherat JU, Bignon Y-J, Blok MJ, Bobisse S, Borrego S, Castellano M, Chanson P, Chiara M-D, Corssmit EPM, Giacchè M, de Krijger RR, Ercolino T, Girerd X, Gómez-García EB, Gómez-Graña A, Guilhem I, Hes FJ, Honrado E, Korpershoek E, Lenders JWM, Letón R, Mensenkamp AR, Merlo A, Mori L, Murat A, Pierre P, Plouin P-F, Prodanov T, Quesada-Charneco M, Qin N, Rapizzi E, Raymond V, Reisch N, Roncador G, Ruiz-Ferrer M, Schillo F, Stegmann APA, Suarez C, Taschin E, Timmers HJLM, Tops CMJ, Urioste M, Beuschlein F, Pacak K, Mannelli M, Dahia PLM, Opocher G, Eisenhofer G, Gimenez-Roqueplo AP, Robledo M. MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma. Clin Cancer Res 2012; 18: 2828-2837
13 Singer J, Koch CA, Kassahun W, Lamesch P, Eisenhofer G, Kluge R, Lincke T, Seiwerts M, Borte G, Schierle K, Paschke R. A patient with a large recurrent pheochromocytoma demonstrating the pitfalls of diagnosis. Nat Rev Endocrinol 2011; 7: 749-755
14 Majumdar S, Friedrich CA, Koch CA, Megason GC, Fratkin JD, Moll GW. Compound heterozygous mutation with a novel splice donor region DNA sequence variant in the succinate dehydrogenase subunit B gene in malignant paraganglioma. Pediatr Blood Cancer 2011; 54: 473-475
15 Aggarwal S, Guleria S, Misra MC, Goswami R, Seth A, Kumar S. Transperitoneal, transmesocolic approach for laparoscopic excision of an extra-adrenal pheochromocytoma. J Laparoendosc Adv Surg Tech A 2006; 16: 261-263
16 Allemann P, Perretta S, Marescaux J. Surgical access to the adrenal gland: the quest for a “no visible scar” approach. Surg Oncol 2009; 18: 131-137
17 Walz MK, Alesina PF, Wenger FA, Deligiannis A, Szuczik E, Petersenn S, Ommer A, Groeben H, Peitgen K, Janssen OE, Philipp T, Neumann HP, Schmid KW, Mann K. Posterior retroperitoneoscopic adrenalectomy – results of 560 procedures in 520 patients. Surgery 2006; 140: 943-948 discussion 948–950
18 Lee CR, Walz MK, Park S, Park JH, Jeong JS, Lee SH, Kang SW, Jeong JJ, Nam KH, Chung WY. A comparative study of the transperitoneal and posterior retroperitoneal approaches for laparoscopic adrenalectomy for adrenal tumors. Ann Surg Oncol 2012; 19: 2629-2634
19 Pham TH, Moir C, Thompson GB, Zarroug AE, Hamner CE, Farley D, van Heerden J, Lteif AN, Young Jr WF. Pheochromocytoma and paraganglioma in children: a review of medical and surgical management at a tertiary care center. Pediatrics 2006; 118: 1109-1117
20 Taieb D, Sebag F, Barlier A, Tessonnier L, Palazzo FF, Morange I, Niccoli-Sire P, Fakhry N, De Micco C, Cammilleri S, Enjalbert A, Henry JF, Mundler O. ¹⁸F-FDG avidity of pheochromocytomas and paragangliomas: a new molecular imaging signature?. J Nucl Med 2009; 50: 711-717
21 Cascon A, Pita G, Burnichon N, Landa I, Lopez-Jimenez E, Montero-Conde C, Leskelä S, Leandro-García LJ, Letón R, Rodríguez-Antona C, Díaz JA, López-Vidriero E, González-Neira A, Velasco A, Matias-Guiu X, Gimenez-Roqueplo AP, Robledo M. Genetics of pheochromocytoma and paraganglioma in Spanish patients. J Clin Endocrinol Metab 2009; 94: 1701-1705
22 Fonte JS, Robles JF, Chen CC, Reynolds J, Whatley M, Ling A, Mercado-Asis LB, Adams KT, Martucci V, Fojo T, Pacak K. False-negative (1)(2)(3)I-MIBG SPECT is most commonly found in SDHB-related pheochromocytoma or paraganglioma with high frequency to develop metastatic disease. Endocr Relat Cancer 2012; 19: 83-93
23 Lefebvre S, Borson-Chazot F, Boutry-Kryza N, Wion N, Schillo F, Peix JL, Brunaud L, Finat A, Calender A, Giraud S. Screening of mutations in genes that predispose to hereditary paragangliomas and pheochromocytomas. Horm Metab Res 2012; 44: 334-338
24 Takeichi N, Midorikawa S, Watanabe A, Naing BT, Tamura H, Wakakuri-Kano T, Ishizaki A, Sugihara H, Nissato S, Saito Y, Aita Y, Ishii KA, Igarashi T, Kawakami Y, Hara H, Ikeda T, Shimizu K, Suzuki S, Shimano H, Kawamoto M, Shimada T, Watanabe T, Oikawa S, Takekoshi K. Identical germline mutations in the TMEM127 gene in two unrelated Japanese patients with bilateral pheochromocytoma. Clin Endocrinol (Oxf) 2012; 77: 707-714
25 Iacobone M, Schiavi F, Bottussi M, Taschin E, Bobisse S, Fassina A, Opocher G, Favia G. Is genetic screening indicated in apparently sporadic pheochromocytomas and paragangliomas?. Surgery 2011; 150: 1194-1201
26 Goffredo P, Sosa JA, Roman SA. Malignant pheochromocytoma and paraganglioma: a population level analysis of long-term survival over two decades. J Surg Oncol 2013; 107: 659-664
27 Szalat A, Fraenkel M, Doviner V, Salmon A, Gross DJ. Malignant pheochromocytoma: predictive factors of malignancy and clinical course in 16 patients at a single tertiary medical center. Endocrine 2011; 39: 160-166
28 Gimm O, DeMicco C, Perren A, Giammarile F, Walz MK, Brunaud L. Malignant pheochromocytomas and paragangliomas: a diagnostic challenge. Langenbecks Arch Surg 2012; 397: 155-177
29 Moskovic DJ, Smolarz JR, Stanley D, Jimenez C, Williams MD, Hanna EY, Kupferman ME. Malignant head and neck paragangliomas: is there an optimal treatment strategy?. Head Neck Oncol 2010; 2: 23
30 Ayala-Ramirez M, Feng L, Johnson MM, Ejaz S, Habra MA, Rich T, Busaidy N, Cote GJ, Perrier N, Phan A, Patel S, Waguespack S, Jimenez C. Clinical risk factors for malignancy and overall survival in patients with pheochromocytomas and sympathetic paragangliomas: primary tumor size and primary tumor location as prognostic indicators. J Clin Endocrinol Metab 2011; 96: 717-725
31 Van Slycke S, Caiazzo R, Pigny P, Cardot-Bauters C, Arnalsteen L, D’Herbomez M, Leteurte E, Rouaix-Emery N, Ernst O, Huglo D, Vantyghem MC, Wemwau JL, Carnaille B, Pattou F. Local-regional recurrence of sporadic or syndromic abdominal extra-adrenal paraganglioma: incidence, characteristics, and outcome. Surgery 2009; 146: 986-992
32 Edstrom Elder E, Hjelm Skog AL, Hoog A, Hamberger B. The management of benign and malignant pheochromocytoma and abdominal paraganglioma. Eur J Surg Oncol 2003; 29: 278-283
33 Cunningham SC, Suh HS, Winter JM, Montgomery E, Schulick RD, Cameron JL, Yeo CJ. Retroperitoneal paraganglioma: single-institution experience and review of the literature. J Gastrointest Surg 2006; 10: 1156-1163
34 Eisenhofer G, Lenders JW, Siegert G, Bornstein SR, Friberg P, Milosevic D, Manelli M, Linehan WM, Adams K, Timmers HJ, Pacak K. Plasma methoxytyramine: a novel biomarker of metastatic pheochromocytoma and paraganglioma in relation to established risk factors of tumour size, location and SDHB mutation status. Eur J Cancer 2011; 48: 1739-1749
35 Korevaar TI, Grossman AB. Pheochromocytomas and paragangliomas: assessment of malignant potential. Endocrine 2011; 40: 354-365
36 Shen WT, Sturgeon C, Clark OH, Duh QY, Kebebew E. Should pheochromocytoma size influence surgical approach? A comparison of 90 malignant and 60 benign pheochromocytomas. Surgery 2004; 136: 1129-1137
37 Feng F, Zhu Y, Wang X, Wu Y, Zhou W, Jin X, Zhang R, Sun F, Kasoma Z, Shen Z. Predictive factors for malignant pheochromocytoma: analysis of 136 patients. J Urol 2011; 185: 1583-1590
38 Clarke MR, Weyant RJ, Watson CG, Carty SE. Prognostic markers in pheochromocytoma. Hum Pathol 1998; 29: 522-526
39 Amar L, Servais A, Gimenez-Roqueplo AP, Zinzindohoue F, Chatellier G, Plouinr PF. Year of diagnosis, features at presentation, and risk of recurrence in patients with pheochromocytoma or secreting paraganglioma. J Clin Endocrinol Metab 2005; 90: 2110-2116
40 Gimenez-Roqueplo AP, Favier J, Rustin P, Rieubland C, Crespin M, Nau V, Khau Van Kien P, Corvol P, Plouin PF, Jeunemaitre X. Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. Cancer Res 2003; 63: 5615-5621
41 Thompson LD. 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 2002; 26: 551-566
42 Laird AM, Gauger PG, Doherty GM, Miller BS. Paraganglioma: not just an extra-adrenal pheochromocytoma. Langenbecks Arch Surg 2012; 397: 247-253
43 Leung K, Stamm M, Raja A, Low G. Pheochromocytoma: the range of appearances on ultrasound, CT, MRI, and functional imaging. Am J Roentgenol 2013; 200: 370-378
44 Gimenez-Roqueplo AP, Caumont-Prim A, Houzard C, Hignette C, Hernigou A, Halimi P, Niccoli P, Leboulleux S, Amar L, Borson-Chazot F, Cardot-Bauters C, Delemer B, Chabolle F, Libe R, Peitzch M, Peyrard S, Tenenbaum F, Plouin PF, Chatellier G, Rohmer V. Imaging work-up for screening of paraganglioma and pheochromocytoma in SDHx mutation carriers: a multicenter prospective study from the PGL.EVA Investigators. J Clin Endocrinol Metab 2013; 98: E162-E173
45 Castro-Vega LJ, Buffet A, De Cubas AA, Cascon A, Menara M, Khalifa E, Amar L, Azriel S, Bourdeau I, Chabre O, Currás-Freixes M, Franco-Vidal V, Guillaud-Bataille M, Simian C, Morin A, Letón R, Gómez-Graña 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 2014; 23: 2440-2446

Supplementary Material

Supporting Information