Skip to main content
SpringerLink
Log in

Pheochromocytoma in MEN 2A Syndrome. Study of 54 Patients

  • Published:
World Journal of Surgery Aims and scope Submit manuscript

Abstract

Background

Pheochromocytoma occurs in nearly 50% of MEN 2A (multiple endocrine neoplasia, type 2A) cases. Many issues related to this tumor are still the subject of debate: the diagnostic management in patients who have had positive genetic study results (RET mutation), variations related to mutation, the best surgical option, and the real relapse rate during long-term follow-up. The aim of this study is to present our experience with this unusual disease, looking for answers to some of these questions.

Patients and methods

Of 169 patients belonging to 19 MEN 2A families, 54 (32%) presented with pheochromocytoma. The following variables have been studied: (1) clinical and diagnostic data [age, mutation, clinical features, results of catecholamines and catabolites in a 24-h urine sample, computerized tomography (CT) scan and iodine-131 meta-iodobenzylguanidine (MIBG) scintigraphy results, and the means of diagnostic, clinical, or genetic screening]; (2) surgical treatment; and (3) follow-up and recurrence. The mean follow-up time was 92.5 months (range: 12–120 months).

Results

The mean age of the 54 patients was 37.9 years (range: 14–71 years); 33 were women. Most (96.3%) mutations were found in exon 11. The most frequent mutations were Cys634Tyr (in 33 cases [61.1%]) and Cys634Arg (in 14 [25.9%]). The diagnosis of pheocromocytoma was made after the diagnosis of MTC in 26 cases (48.2%), simultaneously in 21 (38.9%), and prior in the 7 remaining cases (12.9%). At the time of diagnosis 28 patients (51.8%) were asymptomatic and 26 (48.2%) had clinical features related to pheochromocytoma. In 6 patients (11.1%), the values of catecholamines and catabolites in urine were normal. In the cases with high values, the most useful isolated determination was that of metanephrines (82%), followed by adrenaline (76%). The CT scan did not provide a correct diagnosis in 6 patients with bilateral lesions, and one patient with a bilateral tumor was not diagnosed by MIBG. The combination of CT scan and MIBG diagnosed 100% of cases. The pheochromocytoma was bilateral in 27 cases, with a total number of 81 pathological glands detected. A laparascopic approach was used in 30 cases and a laparotomy in 24. The mean tumor size was 4.5 cm (range: 1–18 cm). Five patients with unilateral resection relapsed (18.5%), and the mean relapse time was 43.2 months (range: 12–120 months). There was a greater frequency of pheochromocytoma in those subjects who had the Cys634Arg mutation (p < 0.03). In addition, the Cys634Arg mutation is more frequent in bilateral cases. There are no prognostic factors for recurrence.

Conclusions

Pheochromocytoma in MEN 2A is related to the type of mutation, which can be early onset and is frequently asymptomatic. Its diagnosis requires catecholamines determinations as well as a CT scan. Correct diagnosis of bilaterality is established by CT and MIBG. Laparoscopic adrenalectomy is the treatment of choice.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Casanova S, Rosenberg-Bourgin M, Farkas D, Calmettes C, Feingold N, Heshmati HM et al (1993) Pheochromocytoma in multiple endocrine neoplasia type 2A: survey of 100 cases. Clin Endocrinol 38:531–537

    Article  CAS  Google Scholar 

  2. Modigliani E, Vasen HM, Rue K, Dralle H, Frilling A et al (1995) Pheochromocytoma in multiple endocrine neoplasia type 2A: European study. The Euromen Study Group. J Intern Med 238:363–367

    PubMed  CAS  Google Scholar 

  3. Toledo SPA, Cortina MA, Toledo RA (2006) Impact of RET protooncogen analysis on the management of multiple endocrine neoplasia type 2. Clinics 61:59–70

    Article  PubMed  Google Scholar 

  4. Brandi ML, Gagel RF, Angeli A, Bilerkian SP, Beck-Peccoz P et al (2001) Guidelines for diagnosis and therapy of MEN type 1 and 2. J Clin Endocrinol Metab 86:5658–5671

    Article  PubMed  CAS  Google Scholar 

  5. Gimm O, Koch CA, Januszewicz A, Opocher G, Neumann HP (2004) The genetic basis of pheochromocytoma. Front Horm Res 31:45–60

    Article  PubMed  CAS  Google Scholar 

  6. Howe JR, Norton JA, Wells SA Jr (1993) Prevalence of pheochromocytoma and hyperparathyroidism in multiple endocrine neoplasia type 2A: results of long-term follow-up. Surgery 114:1070–1077

    PubMed  CAS  Google Scholar 

  7. Nguyen L, Niccoli-Sire P, Caron P, Bastie D, Maes B et al (2001) Pheochromocytoma in multiple endocrine neoplasia type 2: a prospective study. Eur J Endocrinol 144:37–44

    Article  PubMed  CAS  Google Scholar 

  8. Mulligan LM, Eng C, Healey CS et al (1994) Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. Nat Genet 6:70–74

    Article  PubMed  CAS  Google Scholar 

  9. Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G et al (1996) The realationship between specific RET protooncogen mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET consortium analysis. JAMA 276:1575–1579

    Article  PubMed  CAS  Google Scholar 

  10. Neumann HP, Bausch B, McWhinney SR, Bender BU, Gimm O, Franke G et al (2002) Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 346:1459–1466

    Article  PubMed  CAS  Google Scholar 

  11. Machens A, Brauckhoff M, Holzhausen H et al (2005) Codon-specific development of pheochromocytoma in multiple endocrine neoplasia type 2. J Clin Endocrinol Metab 90:3999–4003

    Article  PubMed  CAS  Google Scholar 

  12. Quayle FJ, Fialkowski EA, Benveniste R, Moley JF (2007) Pheochromocytoma penetrance varies by RET mutation in MEN 2A. Surgery 142:800–805

    Article  PubMed  Google Scholar 

  13. Frank-Raue K, Kratt T, Hopner W, Buhr H, Ziegler R, Rue F (1996) Diagnosis and management of pheochromocytomas in patients with multiple endocrine neoplasia type 2—relevance of specific mutations in the RET protooncogene. Eur J Endocrinol 135:222–225

    PubMed  CAS  Google Scholar 

  14. Inabnet WB, Caragliano P, Pertsemlidis D (2000) Pheochromocytoma: inherited associations, bilaterality and cortex preservation. Surgery 128:1007–1011

    Article  PubMed  CAS  Google Scholar 

  15. Neumann HP, Berger DP, Sigmund G, Blum U et al (1993) Pheochromocytomas, multiple endocrine neoplasia and von Hippel-Lindau disease. N Engl J Med 329:1531–1538

    Article  PubMed  CAS  Google Scholar 

  16. Brunt M, Lairmore TC, Doherty GM, Quasebarth RN, DeBenedetti M, Moley JF (2002) Adrenalectomy for familial pheochromocytoma in the laparoscopic era. Ann Surg 235:713–721

    Article  PubMed  Google Scholar 

  17. Eisenhofer G, Walther MM, Huynh TT et al (2001) Pheochromocytomas in von Hippel-Lindau syndrome and multiple endocrine neoplasia type 2 display distinct biochemical and clinical phenotypes. J Clin Endocrinol Metab 86:1999–2008

    Article  PubMed  CAS  Google Scholar 

  18. Kaltsas GA, Papadogias D, Grossman AB (2004) The clinical presentation (symptoms and signs) of sporadic and familial chromaffin cell tumours (pheochromocytomas and paragangliomas). Front Horm Res 31:61–75

    Article  PubMed  Google Scholar 

  19. Pomares FJ, Cañas R, Rodriguez JM, Hernandez AM, Parrilla P, Tebar FJ (1998) Differences between sporadic and multiple endocrine neoplasia type 2A phaechromocytoma. Clin Endocrinol 48:195–200

    Article  CAS  Google Scholar 

  20. Peplinski GR, Norton JA (1994) The predictive value of diagnostic tests for pheochromocytoma. Surgery 116:1101–1109 discussion 1109–1110

    PubMed  CAS  Google Scholar 

  21. Eisenhofer G, Lenders JWWM, Linehan WM, Walter MM et al (1999) Plasma normetanephrine and metanephrine for detecting pheochromocytoma in von Hippel-Lindau disease and multiple endocrione neoplasia type 2A. N Engl J Med 340:1872–1879

    Article  PubMed  CAS  Google Scholar 

  22. Pacak K, Ilias I, Adams KT, Eisenhofer G (2005) Biochemical diagnosis, localization and management of pheochromocytoma: focus on multiple endocrine neoplasia type 2 in relation to other hereditary syndromes and sporadic forms of the tumour. J Intern Med 257:60–68

    Article  PubMed  CAS  Google Scholar 

  23. Maia AL, Gras JL, Puñales MK (2005) Neoplasia endócrina múltipla tipo 2. Arq Bras Endocrinol Metab 49:725–734

    Google Scholar 

  24. Tibblin S, Dymling J-F, Ingemansson S, Telenius-Berg M (1983) Unilateral versus bilateral adrenalectomy in multiple endocrine neoplasia IIA. World J Surg 7:201–208

    Article  PubMed  CAS  Google Scholar 

  25. Ilias I, Pacak K (2004) Current approach and recommended algorithm for the diagosis and localization of pheochromocytoma. J Clin Endocrinol Metab 89:479–491

    Article  PubMed  CAS  Google Scholar 

  26. Mayo-Smith VW, Boland GW, Noto RB et al (2001) State of the art adrenal imaging. Radiographics 21:995–1012

    PubMed  CAS  Google Scholar 

  27. Walther MM (2002) New therapeutic and surgical approaches for sporadic and familial pheochromocytoma. Ann N Y Acad Sci 970:41–53

    Article  PubMed  Google Scholar 

  28. Walz MK, Alesina PF, Wenger FA, Koch JA et al (2006) Laparoscopic and retroperitoneoscopic treatment of pheochromocytomas and retroperitoneal paragangliomas: results of 161 tumours in 126 patients. World J Surg 30:899–908

    Article  PubMed  Google Scholar 

  29. Brauckhoff M, Gimm O, Dralle H (2004) Preoperative and surgical therapy in sporadic and familial pheochromocytoma. Front Horm Res 31:121–144

    Article  PubMed  Google Scholar 

  30. Hartmunt PH, Neumann H, Reincke M, Bender BU et al (1999) Preserved adrenocortical function after laparoscopic bilateral adrenal sparing surgery for hereditary pheochromocytoma. J Clin Endocrinol Metab 84:2608–2610

    Article  Google Scholar 

  31. Asari R, Scheuba C, Kaczirek K, Niederle B (2006) Estimated risk of pheochromocytoma recurrence after adrenal-sparing in patients with multiple endocrine neoplasia type 2A. Arch Surg 141:1199–1205

    Article  PubMed  CAS  Google Scholar 

  32. Van Heerden JA, Sizemore GW, Carney JA et al (1985) Bilateral subtotal adrenal resection for bilateral pheochromocytomas in multiple endocrine neoplasia, type IIa: a case report. Surgery 98:363–366

    PubMed  Google Scholar 

  33. Van Heerden JA, Sizemore GW, Carney JA et al (1984) Surgical management of the adrenal glands in the multiple endocrine neoplasia type II syndrome. World J Surg 8:612–662

    Article  PubMed  Google Scholar 

  34. Lairmore TC, Ball DW, Baylin SB, Wells SA (1993) Management of pheochromocytoma in patients with multiple neoplasia type 2 syndromes. Ann Surg 217:595–601

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Endocrine Surgery Unit, Virgen de la Arrixaca University Hospital, 30120, Murcia, Spain

    Jose M. Rodriguez, Maria Balsalobre, Antonio Ríos, Nuria M. Torregrosa, Javier Tebar & Pascual Parrilla

  2. Endocrine Surgery Unit, La Fé University Hospital, 46009, Valencia, Spain

    Jose L. Ponce

Authors
  1. Jose M. Rodriguez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maria Balsalobre
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jose L. Ponce
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Antonio Ríos
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nuria M. Torregrosa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Javier Tebar
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Pascual Parrilla
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jose M. Rodriguez.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rodriguez, J.M., Balsalobre, M., Ponce, J.L. et al. Pheochromocytoma in MEN 2A Syndrome. Study of 54 Patients. World J Surg 32, 2520–2526 (2008). https://doi.org/10.1007/s00268-008-9734-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00268-008-9734-2

Keywords

Search

Navigation