Skip to main content
SpringerLink
Log in

MGMT immunoexpression in aggressive pituitary adenoma and carcinoma

  • Published:
Pituitary Aims and scope Submit manuscript

Abstract

Recent case reports have documented the efficacy of temozolomide therapy in some aggressive pituitary adenomas and pituitary carcinomas resistant to multimodality therapy. Evidence suggests that low O6-methylguanine-DNA methyltransferase (MGMT) immunoexpression correlates with response to temozolomide chemotherapy. Herein, we aimed to study MGMT immunoexpression in a spectrum of pituitary tumors, indolent, aggressive and malignant. A literature review of the use of temozolomide in pituitary tumors was also performed. Immunohistochemistry for MGMT was performed on 60 pituitary tumors identified in the Mayo Clinic Tissue Registry and the consultation files of one of us (BWS). The group included 30 pituitary carcinomas (15 ACTH, 10 PRL, 1 FSH/LH, 1 TSH, 1 silent subtype 3 and 2 null cell). Tissue from recurrences was available in 17 cases. In addition, 30 functionally different pituitary adenomas were studied, including 15 invasive and 15 non-invasive adenomas. Overall, 32 cases of pituitary tumors (54%) demonstrated low MGMT immunoexpression. This included 17 of 30 (57%) carcinomas, 9 of 15 (60%) invasive adenomas, and 6 of 15 cases (40%) of non-invasive pituitary adenomas. There was no significant change in MGMT immunoexpression between primary and recurrent tumors. Prolactin-producing carcinomas had the highest proportion of tumors (80%) with low expression. A significant proportion of pituitary adenomas and carcinomas demonstrate low MGMT immunoexpression. In an effort to anticipate the likelihood of a temozolomide response, all cases of aggressive pituitary tumors should be assessed for MGMT expression.

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

Similar content being viewed by others

References

  1. Fadul CE, Kominsky AL, Meyer LP, Kingman LS, Kinlaw WB, Rhodes CH, Eskey CJ, Pepin SE, Simmons NE (2004) Pituitary carcinomas respond to temozolomide (abstract TA-18). J Neurooncol 6(4):374. doi:10.1215/s1152851704100148

    Google Scholar 

  2. Fadul CE, Kominsky AL, Meyer LP, Kingman LS, Kinlaw WB, Rhodes CH, Eskey CJ, Simmons NE (2006) Long-term response of pituitary carcinoma to temozolomide. Report of two cases. J Neurosurg 105(4):621–626

    Article  PubMed  Google Scholar 

  3. Guzel A, Tatli M, Senturk S, Guzel E, Cayli SR, Sav A (2008) Pituitary carcinoma presenting with multiple metastases: case report. J Child Neurol 23(12):1467–1471

    Article  PubMed  Google Scholar 

  4. Kaltsas GA, Grossman AB (1998) Malignant pituitary tumours. Pituitary 1(1):69–81

    Article  CAS  PubMed  Google Scholar 

  5. Kaltsas GA, Mukherjee JJ, Plowman PN, Monson JP, Grossman AB, Besser GM (1998) The role of cytotoxic chemotherapy in the management of aggressive and malignant pituitary tumors. J Clin Endocrinol Metab 83(12):4233–4238

    Article  CAS  PubMed  Google Scholar 

  6. Lim S, Shahinian H, Maya MM, Yong W, Heaney AP (2006) Temozolomide: a novel treatment for pituitary carcinoma. Lancet Oncol 7(6):518–520

    Article  PubMed  Google Scholar 

  7. McCormack AI, McDonald KL, Gill AJ, Clark SJ, Burt MG, Campbell KA, Braund WJ, Little NS, Cook RJ, Grossman AB, Robinson BG, Clifton-Bligh RJ (2009) Low O6-methylguanine-DNA methyltransferase (MGMT) expression and response to temozolomide in aggressive pituitary tumours. Clin Endocrinol 71(2):226–233

    Article  CAS  Google Scholar 

  8. Mohammed S, Kovacs K, Mason W, Smyth H, Cusimano MD (2009) Use of temozolomide in aggressive pituitary tumors: case report. Neurosurgery 64(4):E773–E774 discussion E774

    Article  PubMed  Google Scholar 

  9. Pernicone PJ, Scheithauer BW, Sebo TJ, Kovacs KT, Horvath E, Young WF Jr, Lloyd RV, Davis DH, Guthrie BL, Schoene WC (1997) Pituitary carcinoma: a clinicopathologic study of 15 cases. Cancer 79(4):804–812

    Article  CAS  PubMed  Google Scholar 

  10. Ragel BT, Couldwell WT (2004) Pituitary carcinoma: a review of the literature. Neurosurg Focus 16(4):E7

    Article  PubMed  Google Scholar 

  11. Zhu Y, Shaninian H, Hakimian B, Bonert V, Lim S, Heaney AP (2004) Temodar: novel treatment for pituitary carcinoma (abstract). US Endocr Soc 138:43–45

    Google Scholar 

  12. Kaltsas GA, Nomikos P, Kontogeorgos G, Buchfelder M, Grossman AB (2005) Clinical review: diagnosis and management of pituitary carcinomas. J Clin Endocrinol Metab 90(5):3089–3099

    Article  CAS  PubMed  Google Scholar 

  13. Daly AF, Rixhon M, Adam C, Dempegioti A, Tichomirowa MA, Beckers A (2006) High prevalence of pituitary adenomas: a cross-sectional study in the province of liege, Belgium. J Clin Endocrinol Metab 91(12):4769–4775

    Article  CAS  PubMed  Google Scholar 

  14. Moyes VJ, Alusi G, Sabin HI, Evanson J, Berney DM, Kovacs K, Monson JP, Plowman PN, Drake WM (2009) Treatment of nelson’s syndrome with temozolomide. Eur J Endocrinol 160(1):115–119

    Article  CAS  PubMed  Google Scholar 

  15. Esteller M, Hamilton SR, Burger PC, Baylin SB, Herman JG (1999) Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res 59(4):793–797

    CAS  PubMed  Google Scholar 

  16. Esteller M, Garcia-Foncillas J, Andion E, Goodman SN, Hidalgo OF, Vanaclocha V, Baylin SB, Herman JG (2000) Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med 343(19):1350–1354

    Article  CAS  PubMed  Google Scholar 

  17. Hegi ME, Diserens AC, Godard S, Dietrich PY, Regli L, Ostermann S, Otten P, Van Melle G, de Tribolet N, Stupp R (2004) Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide. Clin Cancer Res 10(6):1871–1874

    Article  CAS  PubMed  Google Scholar 

  18. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352(10):997–1003

    Article  CAS  PubMed  Google Scholar 

  19. Kouvaris JR, Miliadou A, Kouloulias VE, Kolokouris D, Balafouta MJ, Papacharalampous XN, Vlahos LJ (2007) Phase II study of temozolomide and concomitant whole-brain radiotherapy in patients with brain metastases from solid tumors. Onkologie 30(7):361–366

    Article  CAS  PubMed  Google Scholar 

  20. Stupp R, Gander M, Leyvraz S, Newlands E (2001) Current and future developments in the use of temozolomide for the treatment of brain tumours. Lancet Oncol 2(9):552–560

    Article  CAS  PubMed  Google Scholar 

  21. Ekeblad S, Sundin A, Janson ET, Welin S, Granberg D, Kindmark H, Dunder K, Kozlovacki G, Orlefors H, Sigurd M, Oberg K, Eriksson B, Skogseid B (2007) Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res 13(10):2986–2991

    Article  CAS  PubMed  Google Scholar 

  22. Kulke MH, Stuart K, Enzinger PC, Ryan DP, Clark JW, Muzikansky A, Vincitore M, Michelini A, Fuchs CS (2006) Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol 24(3):401–406

    Article  CAS  PubMed  Google Scholar 

  23. Syro LV, Ortiz LD, Scheithauer BW, Lloyd RV, Lau Q, Gonzalez R, Uribe H, Cusimano M, Kovacs K, Horvath E (in press) Treatment of pituitary neoplasms with temozolomide: a review. Cancer

  24. Rodriguez FJ, Thibodeau SN, Jenkins RB, Schowalter KV, Caron BL, O’Neill BP, James CD, Passe S, Slezak J, Giannini C (2008) MGMT immunohistochemical expression and promoter methylation in human glioblastoma. Appl Immunohistochem Mol Morphol 16(1):59–65

    CAS  PubMed  Google Scholar 

  25. Gerson SL (2002) Clinical relevance of MGMT in the treatment of cancer. J Clin Oncol 20(9):2388–2399

    Article  CAS  PubMed  Google Scholar 

  26. Gerson SL (2004) MGMT: its role in cancer aetiology and cancer therapeutics. Nat Rev 4(4):296–307

    CAS  Google Scholar 

  27. Jacinto FV, Esteller M (2007) MGMT hypermethylation: a prognostic foe, a predictive friend. DNA repair 6(8):1155–1160

    Article  CAS  PubMed  Google Scholar 

  28. Widhalm G, Wolfsberger S, Preusser M, Woehrer A, Kotter MR, Czech T, Marosi C, Knosp E (2009) O(6)-methylguanine DNA methyltransferase immunoexpression in nonfunctioning pituitary adenomas: are progressive tumors potential candidates for temozolomide treatment? Cancer 115(5):1070–1080

    Article  CAS  PubMed  Google Scholar 

  29. Everhard S, Kaloshi G, Criniere E, Benouaich-Amiel A, Lejeune J, Marie Y, Sanson M, Kujas M, Mokhtari K, Hoang-Xuan K, Delattre JY, Thillet J (2006) MGMT methylation: a marker of response to temozolomide in low-grade gliomas. Ann Neurol 60(6):740–743

    Article  CAS  PubMed  Google Scholar 

  30. Halford S, Rowan A, Sawyer E, Talbot I, Tomlinson I (2005) O(6)-methylguanine methyltransferase in colorectal cancers: Detection of mutations, loss of expression, and weak association with G:C > A:T transitions. Gut 54(6):797–802

    Article  CAS  PubMed  Google Scholar 

  31. Koga Y, Kitajima Y, Miyoshi A, Sato K, Kitahara K, Soejima H, Miyazaki K (2005) Tumor progression through epigenetic gene silencing of O(6)-methylguanine-DNA methyltransferase in human biliary tract cancers. Ann Surg Oncol 12(5):354–363

    Article  PubMed  Google Scholar 

  32. Bello MJ, De Campos JM, Isla A, Casartelli C, Rey JA (2006) Promoter CpG methylation of multiple genes in pituitary adenomas: frequent involvement of caspase-8. Oncol Rep 15(2):443–448

    CAS  PubMed  Google Scholar 

  33. Chinot OL, Barrie M, Fuentes S, Eudes N, Lancelot S, Metellus P, Muracciole X, Braguer D, Ouafik L, Martin PM, Dufour H, Figarella-Branger D (2007) Correlation between O6-methylguanine-DNA methyltransferase and survival in inoperable newly diagnosed glioblastoma patients treated with neoadjuvant temozolomide. J Clin Oncol 25(12):1470–1475

    Article  CAS  PubMed  Google Scholar 

  34. Chakravarti A, Erkkinen MG, Nestler U, Stupp R, Mehta M, Aldape K, Gilbert MR, Black PM, Loeffler JS (2006) Temozolomide-mediated radiation enhancement in glioblastoma: a report on underlying mechanisms. Clin Cancer Res 12(15):4738–4746

    Article  CAS  PubMed  Google Scholar 

  35. Kovacs K, Scheithauer BW, Lombardero M, McLendon RE, Syro LV, Uribe H, Ortiz LD, Penagos LC (2008) MGMT immunoexpression predicts responsiveness of pituitary tumors to temozolomide therapy. Acta Neuropathol 115(2):261–262

    Article  PubMed  Google Scholar 

  36. Friedman HS, McLendon RE, Kerby T, Dugan M, Bigner SH, Henry AJ, Ashley DM, Krischer J, Lovell S, Rasheed K, Marchev F, Seman AJ, Cokgor I, Rich J, Stewart E, Colvin OM, Provenzale JM, Bigner DD, Haglund MM, Friedman AH, Modrich PL (1998) DNA mismatch repair and O6-alkylguanine-DNA alkyltransferase analysis and response to temodal in newly diagnosed malignant glioma. J Clin Oncol 16(12):3851–3857

    CAS  PubMed  Google Scholar 

  37. McLendon RE, Cleveland L, Pegram C, Bigner SH, Bigner DD, Friedman HS (1998) Immunohistochemical detection of the DNA repair enzyme O6-methylguanine-DNA methyltransferase in formalin-fixed, paraffin-embedded astrocytomas. Lab Invest 78(5):643–644

    CAS  PubMed  Google Scholar 

  38. Lloyd RV, Kovacs K, Young WFJ, Farrell WE, Asa SL, Trouillas J, Kontogeorgos G, Sano T, Scheithauer BW, Horvath E (2004) Tumours of the pituitary (chapter 1). In: DeLellis RA, Lloyd RV, Heitz PU, Eng C (eds) Pathology and genetics of tumours of endocrine organs—World Health Organization classification of tumours. IARC Press, Lyon, pp 9–47

    Google Scholar 

  39. Hagen C, Schroeder HD, Hansen S, Hagen C, Andersen M (2009) Temozolomide treatment of a pituitary carcinoma and two pituitary macroadenomas resistant to conventional therapy. Eur J Endocrinol 161(4):631–637

    Article  CAS  PubMed  Google Scholar 

  40. Takeshita A, Inoshita N, Taguchi M, Okuda C, Fukuhara N, Oyama K, Ohashi K, Sano T, Takeuchi Y, Yamada S (2009) High incidence of low O(6)-methylguanine DNA methyltransferase expression in invasive macroadenomas of Cushing’s disease. Eur J Endocrinol 161(4):553–559

    Article  CAS  PubMed  Google Scholar 

  41. Kovacs K, Horvath E, Syro LV, Uribe H, Penagos LC, Ortiz LD, Fadul CE (2007) Temozolomide therapy in a man with an aggressive prolactin-secreting pituitary neoplasm: morphological findings. Hum Pathol 38(1):185–189

    Article  CAS  PubMed  Google Scholar 

  42. Syro LV, Uribe H, Penagos LC, Ortiz LD, Fadul CE, Horvath E, Kovacs K (2006) Antitumour effects of temozolomide in a man with a large, invasive prolactin-producing pituitary neoplasm. Clin Endocrinol 65(4):552–553

    Article  Google Scholar 

  43. Neff LM, Weil M, Cole A, Hedges TR, Shucart W, Lawrence D, Zhu JJ, Tischler AS, Lechan RM (2007) Temozolomide in the treatment of an invasive prolactinoma resistant to dopamine agonists. Pituitary 10(1):81–86

    Article  PubMed  Google Scholar 

  44. Idbaih A, Omuro A, Ducray F, Hoang-Xuan K (2007) Molecular genetic markers as predictors of response to chemotherapy in gliomas. Curr Opin Oncol 19(6):606–611

    Article  CAS  PubMed  Google Scholar 

  45. Pollack IF, Hamilton RL, Sobol RW, Burnham J, Yates AJ, Holmes EJ, Zhou T, Finlay JL (2006) O6-methylguanine-DNA methyltransferase expression strongly correlates with outcome in childhood malignant gliomas: results from the CCG-945 cohort. J Clin Oncol 24(21):3431–3437

    Article  CAS  PubMed  Google Scholar 

  46. Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB (1996) Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 93(18):9821–9826

    Article  CAS  PubMed  Google Scholar 

  47. Costello JF, Futscher BW, Tano K, Graunke DM, Pieper RO (1994) Graded methylation in the promoter and body of the O6-methylguanine DNA methyltransferase (MGMT) gene correlates with MGMT expression in human glioma cells. J Biol Chem 269(25):17228–17237

    CAS  PubMed  Google Scholar 

  48. Mollemann M, Wolter M, Felsberg J, Collins VP, Reifenberger G (2005) Frequent promoter hypermethylation and low expression of the MGMT gene in oligodendroglial tumors. Int J Cancer 113(3):379–385

    Article  PubMed  Google Scholar 

  49. Bates AS, Farrell WE, Bicknell EJ, McNicol AM, Talbot AJ, Broome JC, Perrett CW, Thakker RV, Clayton RN (1997) Allelic deletion in pituitary adenomas reflects aggressive biological activity and has potential value as a prognostic marker. J Clin Endocrinol Metab 82(3):818–824

    Article  CAS  PubMed  Google Scholar 

  50. Bugni JM, Han J, Tsai MS, Hunter DJ, Samson LD (2007) Genetic association and functional studies of major polymorphic variants of MGMT. DNA Repair 6(8):1116–1126

    Article  CAS  PubMed  Google Scholar 

  51. Ogino S, Hazra A, Tranah GJ, Kirkner GJ, Kawasaki T, Nosho K, Ohnishi M, Suemoto Y, Meyerhardt JA, Hunter DJ, Fuchs CS (2007) MGMT germline polymorphism is associated with somatic MGMT promoter methylation and gene silencing in colorectal cancer. Carcinogenesis 28(9):1985–1990

    Article  CAS  PubMed  Google Scholar 

  52. Fujimaki T, Ishii H, Matsuno A, Arai H, Nakagomi T (2007) Effectiveness of interferon-beta and temozolomide combination therapy against temozolomide-refractory recurrent anaplastic astrocytoma. World J Surg Oncol 5:89

    Article  PubMed  Google Scholar 

  53. Liu L, Gerson SL (2006) Targeted modulation of MGMT: clinical implications. Clin Cancer Res 12(2):328–331

    Article  CAS  PubMed  Google Scholar 

  54. Tanaka S, Kobayashi I, Utsuki S, Oka H, Yasui Y, Fujii K (2005) Down-regulation of O6-methylguanine-DNA methyltransferase gene expression in gliomas by platinum compounds. Oncol Rep 14(5):1275–1280

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Mrs. Michelle Lemke and Mrs. Denise Chase of Mayo Clinic for their research assistance and secretarial support, respectively.

Author information

Authors and Affiliations

  1. Department of Anatomical Pathology and Cytopathology, Royal Brisbane and Women’s Hospital and Gold Coast Hospital, Queensland, Australia

    Queenie Lau

  2. Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street, SW, Rochester, MN, 55905, USA

    Queenie Lau, Bernd Scheithauer & Ricardo Lloyd

  3. Department of Laboratory Medicine, St. Michael’s Hospital, Toronto, Canada

    Kalman Kovacs & Eva Horvath

  4. Department of Neurosurgery, Hospital Pablo Tobon Uribe and Clinica Medellin, Medellin, Colombia

    Luis V. Syro

Authors
  1. Queenie Lau
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bernd Scheithauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kalman Kovacs
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eva Horvath
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Luis V. Syro
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ricardo Lloyd
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bernd Scheithauer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lau, Q., Scheithauer, B., Kovacs, K. et al. MGMT immunoexpression in aggressive pituitary adenoma and carcinoma. Pituitary 13, 367–379 (2010). https://doi.org/10.1007/s11102-010-0249-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11102-010-0249-0

Keywords

Search

Navigation