Progression Patterns in Non-Contrast-Enhancing Gliomas Support Brain Tumor Responsiveness to Surgical Lesions

Purpose: The overall benefit of surgical treatments for patients with glioma is undisputed. We have shown preclinically that brain tumor cells form a network that is capable of detecting damage to the tumor, and repair itself. The aim of this study was to determine whether a similar mechanism might contribute to local recurrence in the clinical setting. Methods: We evaluated tumor progression patterns of 24 initially non-contrast-enhancing gliomas that were partially resected or biopsied. We measured the distance between the new contrast enhancement developing over time, and prior surgical lesioning, and evaluated tumor network changes in response to sequential resections by quantifying tumor cells and tumor networks with specific stainings against IDH1-R132H. Results: We found that new contrast enhancement appeared within the residual, non-enhancing tumor mass in 21/24 patients (87.5%). The location of new contrast enhancement within the residual tumor region was non-random; it occurred adjacent to the wall of the resection cavity in 12/21 patients (57.1%). Interestingly, the density of the glioma cell network increased in all patient tumors between initial resection or biopsy and recurrence. In line with the histological and radiological malignization, Ki67 expression increased from initial to final resections in 14/17 cases. Conclusion: The non-random distribution of glioma malignization in patients and unidirectional increase of anatomical tumor networks after surgical procedures provides evidence that surgical lesions, in the presence of residual tumor cells, can stimulate local tumor progression and tumor cell network formation. This argues for the development of intraoperative treatments increasing the benefits from surgical resection by specifically disrupting the mechanisms of local recurrence, particularly tumor cell network functionality.