The metastatic infiltration at the metastasis/brain parenchyma-interface is very heterogeneous and has a significant impact on survival in a prospective study

// Laila Siam 1 , Annalen Bleckmann 2, 3 , Han-Ning Chaung 2 , Alexander Mohr 4 , Florian Klemm 2 , Alonso Barrantes-Freer 5 , Raquel Blazquez 2 , Hendrik A. Wolff 6 , Florian Luke 7 , Veit Rohde 1 , Christine Stadelmann 5 , Tobias Pukrop 2, 7 1 Department of Neurosurgery, University Medical Center, Gottingen, Germany 2 Department of Hematology and Medical Oncology, University Medical Center, Gottingen, Germany 3 Department of Medical Statistics, University Medical Center, Gottingen, Germany 4 Department of Neuroradiology, University Medical Center, Gottingen, Germany 5 Institute of Neuropathology, University Medical Center, Gottingen, Germany 6 Department of Radiotherapy and Radiation Oncology, University Medical Center, Gottingen, Germany 7 Department of Internal Medicine III, Hematology and Medical Oncology, University Hospital Regensburg, Regensburg, Germany Correspondence to: Tobias Pukrop, e-mail: tobias.pukrop@ukr.de Keywords: astrocytes, brain metastasis, glial-pseudo capsule, metastatic infiltration, organ-specific defense Received: April 11, 2015      Accepted: June 08, 2015      Published: June 17, 2015 ABSTRACT The current approach to brain metastases resection is macroscopic removal of metastasis until reaching the glial pseudo-capsule (gross total resection (GTR)). However, autopsy studies demonstrated infiltrating metastatic cells into the parenchyma at the metastasis/brain parenchyma (M/BP)-interface. Aims/Methods: To analyze the astrocyte reaction and metastatic infiltration pattern at the M/BP-interface with an organotypic brain slice coculture system. Secondly, to evaluate the significance of infiltrating metastatic tumor cells in a prospective biopsy study. Therefore, after GTR, biopsies were obtained from the brain parenchyma beyond the glial pseudo-capsule and analyzed histomorphologically. Results: The coculture revealed three types of cancer cell infiltration. Interestingly, the astrocyte reaction was significantly different in the coculture with a benign, neuroectodermal-derived cell line. In the prospective biopsy study 58/167 (34.7%) samples revealed infiltrating metastatic cells. Altogether, 25/39 patients (64.1%) had proven to exhibit infiltration in at least one biopsy specimen with significant impact on survival (OS) (3.4 HR; p = 0.009; 2-year OS was 6.6% versus 43.5%). Exceptionally, in the non-infiltrating cohort three patients were long-term survivors. Conclusions: Metastatic infiltration has a significant impact on prognosis. Secondly, the astrocyte reaction at the M/BP-interface is heterogeneous and supports our previous concept of the organ-specific defense against metastatic (organ-foreign) cells.