Background and Purpose Recurrent glioblastoma patients often exhibit regions of diffusion restriction following the initiation of bevacizumab therapy. Studies suggest these regions represent either diffusion restricted necrosis or hypercellular tumor. This study explores autopsy brain specimens and a population analysis of overall survival to determine the identity and implications of such lesions. Methods Autopsies were performed on six recurrent glioblastoma patients on bevacizumab with progressively growing regions of diffusion restriction. ADC values were extracted from regions of both hypercellular tumor and necrosis. A receiver operating characteristic analysis was performed to define optimal ADC thresholds for differentiating tissue types. A retrospective population study was also performed comparing the OS of sixty-four recurrent glioblastoma patients treated with bevacizumab. Patients were separated into three groups: no diffusion restriction, diffusion restriction that appeared and progressed within 5 months of bevacizumab onset, and delayed or stable diffusion restriction. An additional analysis was done assessing tumor O6-methylguanine-DNA-methyltransferase methylation. Results The optimal ADC threshold for differentiation between hypercellularity and necrosis was 0.736×10−3mm2/s. Progressively expanding diffusion restriction was pathologically confirmed to be coagulative necrosis surrounded by viable tumor. Progressive lesions were associated with the worst overall survival while stable lesions showed greatest (p<0.05). Of the 40% of patients with O6-methylguanine-DNA-methyltransferase methylated tumors, none developed diffusion-restricted lesions. Conclusion Progressive diffusion-restricted lesions were pathologically confirmed to be coagulative necrosis surrounded by viable tumor and associated with decreased overall survival. Stable lesions were however associated with increased overall survival. All lesions were associated with O6-methylguanine-DNA-methyltransferase unmethylated tumors.

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