Skip to main content

Advertisement

SpringerLink
Log in

Bilateral Pheochromocytomas in MEN2A Syndrome: A Two-Institution Experience

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

Abstract

Background

Bilateral pheochromocytoma (PHEO) is more frequently found in patients with multiple endocrine neoplasia 2A carrying a RET germline mutation located in codon 634 (C634). However, it is unclear whether different amino acid substitutions within C634 cause differences in bilateral PHEOs expression. We aimed to answer this by pooling data from two Asian institutions.

Methods

Sixty-seven patients had confirmed C634 germline mutation. Age-dependent penetrance of bilateral PHEO was calculated from date of birth to the date when bilateral PHEO was first diagnosed or when the contralateral gland became a PHEO (if the patient already had one adrenal gland removed). Age-dependent penetrance was estimated by the Kaplan–Meier method and compared by log-rank test.

Results

The 4 different amino acid substitutions included C634R (arginine) (n = 19, 28.4 %), C634Y (tyrosine) (n = 36, 38.8 %), C634G (glycine) (n = 4, 6.0 %), and C634W (tryptophan) (n = 8, 11.9 %). The age-related penetrance of PHEO was similar between C634R, C634Y, C634G, and C634W (by age 40, 69.8, 55.2, 25.0, and 56.2 %, respectively) (p = 0.529). However, the age-related penetrance of bilateral PHEO in C634R was significantly higher than C634Y (by age of 40, 59.3 % vs. 25.2 %, p = 0.046) or C634Y, C634G, and C634W combined (59.3 % vs. 21.5 %, p = 0.024). Nevertheless, the accumulative risk of bilateral PHEOs across all four C634 mutations almost approached 100 % over time.

Conclusion

The accumulative risk of bilateral PHEOs almost reached 100 % but its onset was significantly earlier in C634R mutation. These findings implied that those with C634R mutation might benefit from earlier screening of contralateral PHEO than other C634 mutations after an unilateral adrenalectomy.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Asari R, Scheuba C, Kaczirek K, Niederle B (2006) Estimated risk of pheochromocytoma recurrence after adrenal-sparing surgery in patients with multiple endocrine neoplasia type 2A. Arch Surg 141(12):1199–1205 discussion 1205

    Article  CAS  PubMed  Google Scholar 

  2. 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(7):3999–4003

    Article  CAS  PubMed  Google Scholar 

  3. Castinetti F, Qi XP, Walz MK et al (2014) Outcomes of adrenal-sparing surgery or total adrenalectomy in phaeochromocytoma associated with multiple endocrine neoplasia type 2: an international retrospective population-based study. Lancet Oncol 15(6):648–655

    Article  PubMed  Google Scholar 

  4. Lau GS, Lang BH, Lo CY, Tso A, Garcia-Barcelo MM, Tam PK, Lam KS (2009) Prophylactic thyroidectomy in ethnic Chinese patients with multiple endocrine neoplasia type 2A syndrome after the introduction of genetic testing. Hong Kong Med J 15(5):326–331

    PubMed  Google Scholar 

  5. Puñales MK, Graf H, Gross JL, Maia AL (2003) RET codon 634 mutations in multiple endocrine neoplasia type 2: variable clinical features and clinical outcome. J Clin Endocrinol Metab 88(6):2644–2649

    Article  PubMed  Google Scholar 

  6. MEN Consortium of Japan, Imai T, Uchino S, Okamoto T, Suzuki S et al (2013) High penetrance of pheochromocytoma in multiple endocrine neoplasia 2 caused by germ line RET codon 634 mutation in Japanese patients. Eur J Endocrinol 168(5):683–687

    Article  Google Scholar 

  7. Quayle FJ, Fialkowski EA, Benveniste R, Moley JF (2007) Pheochromocytoma penetrance varies by RET mutation in MEN2A. Surgery 142:800–805

    Article  PubMed  Google Scholar 

  8. Lo CY, Wat NM, Lam KY, Tiu SC, Chan J, Lam KS (2003) Multiple endocrine neoplasia type 2A in Chinese families. Clin Endocrinol (Oxf). 58(4):528

    Article  PubMed  Google Scholar 

  9. Zhou Y, Zhao Y, Cui B et al (2007) RET proto-oncogene mutations are restricted to codons 634 and 918 in mainland Chinese families with MEN2A and MEN2B. Clin Endocrinol (Oxf) 67(4):570–576

    CAS  Google Scholar 

  10. Valdés N, Navarro E, Mesa J, Casterás A, Alcázar V, Lamas C, Tébar J, CastaÑo L, Gaztambide S, Forga Llenas L (2014) RET Cys634Arg mutation confers a more aggressive multiple endocrine neoplasia type 2A phenotype than Cys634Tyr mutation. Eur J Endocrinol 172:301–307

    Article  PubMed  Google Scholar 

  11. Ku CF, Lo CY, Chan WF, Chiu SW, Fan ST, Lam KS (2005) Resection of phaeochromocytoma extending into the right atrium in a patient with multiple endocrine neoplasia type 2A. Hong Kong Med J 11(1):59–62

    CAS  PubMed  Google Scholar 

  12. Milos IN, Frank-Raue K, Wohllk N et al (2008) Age-related neoplastic risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germ line RET Cys634Trp (TGC > TGG) mutation. Endocr Relat Cancer 15(4):1035–1041

    Article  CAS  PubMed  Google Scholar 

  13. Eng C, Clayton D, Schuffenecker I et al (1996) The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA 276(19):1575–1579

    Article  CAS  PubMed  Google Scholar 

  14. Yip L, Lee JE, Shapiro SE, Waguespack SG, Sherman SI, Hoff AO, Gagel RF, Arens JF, Evans DB (2004) Surgical management of hereditary pheochromocytoma. J Am Coll Surg 198(4):525–534

    Article  PubMed  Google Scholar 

  15. Rodriguez JM, Balsalobre M, Ponce JL, Ríos A, Torregrosa NM, Tebar J, Parrilla P (2008) Pheochromocytoma in MEN 2A syndrome. Study of 54 patients. World J Surg 32(11):2520–2526. doi:10.1007/s00268-008-9734-2

    Article  PubMed  Google Scholar 

  16. Chang RY, Lang BH, Wong KP, Lo CY (2014) High pre-operative urinary norepinephrine is an independent determinant of peri-operative hemodynamic instability in unilateral pheochromocytoma/paraganglioma removal. World J Surg 38(9):2317–2323. doi:10.1007/s00268-014-2597-9

    Article  PubMed  Google Scholar 

  17. Thosani S, Ayala-Ramirez M, Palmer L et al (2013) The characterization of pheochromocytoma and its impact on overall survival in multiple endocrine neoplasia type 2. J Clin Endocrinol Metab 98(11):E1813–E1819

    Article  CAS  PubMed  Google Scholar 

  18. Castinetti F, Qi XP, Walz MK et al (2014) Outcomes of adrenal-sparing surgery or total adrenalectomy in phaeochromocytoma associated with multiple endocrine neoplasia type 2: an international retrospective population-based study. Lancet Oncol 5(6):648–655

    Article  Google Scholar 

  19. Siqueira DR, Ceolin L, Ferreira CV, Romitti M, Maia SC, Maciel LM, Maia AL (2014) Role of RET genetic variants in MEN2-associated pheochromocytoma. Eur J Endocrinol 170(6):821–828

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Surgery, The University of Hong Kong, Hong Kong, SAR, China

    Brian Hung-Hin Lang, Chung-Yau Lo, Maria-Mercedes Garcia-Barcelo, Kai Pun Wong & Paul K. H. Tam

  2. Department of Surgery, Seoul National University College of Medicine and Hospital, Seoul, Korea

    Hyeong Won Yu & Kyu Eun Lee

  3. Department of Medicine, The University of Hong Kong, Hong Kong, SAR, China

    Yu Cho Woo, Paul C. H. Lee & Karen S. L. Lam

  4. Division of Endocrine Surgery, Department of Surgery, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, SAR, China

    Brian Hung-Hin Lang

Authors
  1. Brian Hung-Hin Lang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hyeong Won Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chung-Yau Lo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kyu Eun Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maria-Mercedes Garcia-Barcelo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yu Cho Woo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Paul C. H. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kai Pun Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Paul K. H. Tam
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Karen S. L. Lam
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Brian Hung-Hin Lang.

Additional information

Brian Hung-Hin Lang and Hyeong Won Yu are co-first authors of this article.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lang, B.HH., Yu, H.W., Lo, CY. et al. Bilateral Pheochromocytomas in MEN2A Syndrome: A Two-Institution Experience. World J Surg 39, 2484–2491 (2015). https://doi.org/10.1007/s00268-015-3117-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00268-015-3117-2

Keywords

Search

Navigation