ORIGINAL PAPER Neural cell adhesion molecule isoform 140 declines with rise of WHO grade in human gliomas and serves as indicator for the invasion zone of multiform glioblastomas and brain metastases Pedro Duenisch • Rupert Reichart • Ulrike Mueller • Michael Brodhun • Rolf Bjerkvig • Bernd Romeike • Jan Walter • Christian Herbold • Christian R. A. Regenbrecht • Rolf Kalff • Susanne A. Kuhn Received: 11 March 2010 / Accepted: 6 April 2010 / Published online: 4 May 2010 Ó Springer-Verlag 2010 Abstract Purpose Gliomas are highly invasive neuroepithelial tumors with a propensity of malignant transformation and very restricted treatment options. The neural cell adhesion molecule (NCAM) modulates cellular migration, prolifer- ation, and synaptic plasticity by homophilic and hetero- philic interactions. Hereby, we investigated its relevance as a glioma tissue marker for the biological aggressiveness of these tumors and compared these features with the carci- noma brain metastasis invasion zone. Materials and methods We analyzed 194 human brain samples. Human tumor-free brain specimens served as control for the white and gray matter. In addition to that, we used human glioblastomas from nude rats. All tissues were investigated immunohistochemically for the expres- sion of the NCAM isoform 140. Additionally, the multi- planar MRI-CT fusion neuronavigation-guided serial stereotactic biopsy was performed and completed by his- topathological workup. Results Human gliomas loose NCAM-140 with the rise of their WHO grade. Meningiomas are NCAM-140 negative. As the most striking feature, human brain metastases and the majority of human glioblastomas of our patients and of nude rats were totally NCAM-140 negative. This NCAM negativity led us to the conclusion of three different main glioblastoma invasion patterns. Surprisingly, the majority of brain metastasis samples that contained surrounding brain parenchyma demonstrated invasive tumor cell nests beyond the sharply demarcated metastasis border. We also found invasive metastatic cell nests outside the contrast enhancing tumor zone by means of the MRI-CT fusion neuronavigation-guided serial stereotactic biopsy. Conclusion The expression of NCAM-140 inversely correlates with the WHO grade of human gliomas. The lost expression of NCAM-140 in human glioblastomas and in brain metastases enables the investigation of the brain– tumor interface and the definition of glioblastoma invasion patterns and shows that brain metastases are more invasive than ever thought. Keywords NCAM Á Glioma Á WHO grade Á Carcinoma brain metastases Á Meningioma Á Brain–tumor interface The authors P. Duenisch, R. Reichart, R. Kalff and S. A. Kuhn contributed equally. P. Duenisch Á R. Reichart Á J. Walter Á C. Herbold Á R. Kalff Á S. A. Kuhn (&) Department of Neurosurgery, Medical Center, Friedrich-Schiller-University, Erlanger Allee 101, 07747 Jena, Germany e-mail: Susanne.Kuhn@med.uni-jena.de U. Mueller SKP Services, Dresden, Germany M. Brodhun Institute of Pathology, Helios Klinikum Erfurt, Erfurt, Germany R. Bjerkvig NorLux Neuro-Oncology Laboratory, Department of Biomedicine, University of Bergen, Bergen, Norway B. Romeike Institute of Pathology, Medical Center of Friedrich-Schiller-University, Jena, Germany C. R. A. Regenbrecht Max-Planck-Institute of Molecular Genetics, Berlin, Germany 123 J Cancer Res Clin Oncol (2011) 137:399–414 DOI 10.1007/s00432-010-0888-6