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Acta Neuropathologica

, Volume 115, Issue 2, pp 249–259 | Cite as

Pitfalls in the assessment of MGMT expression and in its correlation with survival in diffuse astrocytomas: proposal of a feasible immunohistochemical approach

  • David Capper
  • Michel Mittelbronn
  • Richard Meyermann
  • Jens Schittenhelm
Original Paper

Abstract

Immunohistochemical studies showed that O6-methylguanine-DNA methyltransferase (MGMT) protein expression is negatively associated with survival in glioblastomas treated with alkylating agents in accordance with previous results of methylation-specific PCR. Implementation of this data in routine clinical diagnostics is limited due to often inappropriate study designs, e.g. pooling of tumor entities, WHO grades or primary and secondary glioblastomas, disregard concerning the infiltration zone or various epidemiological factors. The aim of our study was to evaluate MGMT expression and its prognostic value taking into consideration the aforementioned deficiencies. For this, 162 astrocytic tumors WHO II–IV (36 diffuse astrocytomas WHO II, 51 anaplastic astrocytomas, 75 primary glioblastomas) as well as 25 glioblastoma infiltration zones and 19 glioblastoma relapses were analyzed for immunohistochemical MGMT protein expression using tissue microarray technique. Expression of MGMT significantly decreased from WHO grade II (25.6%) to glioblastoma (16.8%, p = 0.01) with lowest levels in grade III tumors (10.2%, II/III p < 0.0001). Significant negative associations of MGMT and survival were detected for WHO grade II and IV (p = 0.003 and 0.013). The optimal cut-off value of MGMT positive nuclei in primary glioblastomas discriminating patients with significantly different survival rates was at 15% (Log–Rank p = 0.0002). Individual relapse tumors showed changes of MGMT expression to a varying degree. The infiltration zone demonstrated a significant increase of MGMT (p < 0.0001). We conclude that immunohistochemical MGMT assessment has potential as a powerful diagnostic tool but analysis should only be performed in a grade dependent manner, before radio-/chemotherapy and with special attention to the infiltration zone of diffuse astrocytomas.

Keywords

MGMT Astrocytoma Immunohistochemistry 

Notes

Acknowledgments

We thank R. Ajaaj, G. Tabatabai and F. Stubenvoll for the collection of the clinical data and B. J. Capper for critical reading of the manuscript.

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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • David Capper
    • 1
    • 2
  • Michel Mittelbronn
    • 1
  • Richard Meyermann
    • 1
  • Jens Schittenhelm
    • 1
  1. 1.Institute of Brain ResearchUniversity of TübingenTübingenGermany
  2. 2.Institute of NeuropathologyUniversity of ZürichZürichSwitzerland

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