Multidimensional characterization of supratentorial adult-type diffuse gliomas that migrate to the brainstem

Document Type

Conference Proceeding

Publication Date

6-6-2024

Publication Title

J Neuropathol Exp Neurol

Abstract

Background: We previously showed that cerebral diffuse gliomas usually spread to the brainstem at the final stages of disease, and that this, not tonsillar herniation, most likely accounts for brainstem-type symptoms commonly observed at the end of life (PMID: 31711239). It remains unknown whether glioma cells that spread to the brainstem are different from glioma that remains near the original tumor site (“stationary”). Methods: We analyzed original premortem tumors, postmortem stationary tumors, and postmortem tumors that infiltrated the brainstem from 20 patients (5 IDHmut astrocytomas, 15 IDHwt GBM). Each site was analyzed for expression of key markers by immunohistochemistry, genomic DNA methylation profiling (including deconvolution analysis of immune populations), and whole exome sequencing. Results: Compared to stationary tumors, glioma subclones that migrated to the brainstem had higher Ki67 proliferation indices (P=0.003), expressed fewer mesenchymal markers (P<0.001), lost OLIG2 expression (P<0.001), and were normoxic as indicated by HIF1a (P=0.03). Brainstem tumors also had fewer admixed macrophages and lymphocytes (P<0.05), except for patients who received immunotherapy during their disease courses. In those cases, lymphocytes and macrophages were elevated in the brainstems (but not in stationary tumors) relative to the brainstems of patients without immunotherapy (P<0.01). Microvascular proliferation was not found in any glioma-infiltrated brainstems. Whereas IDHmut astrocytomas retained their methylation profiles, 40% of the RTK-II subset of IDHwt GBM shifted methylation subclass, most commonly to RTK-I. There was no consistent pattern of mutations in brainstem subclones vs. premortem or stationary tumors, and tumor mutation burden was similar in all three settings (P=0.17). Conclusions: Together, these data suggest that, while brainstem subclones mostly retain the molecular patterns of their supratentorial origins, protein expression shifts in consistent patterns, perhaps as a consequence of the glioma cells having moved to a new microenvironment. This study sheds new light on the characteristics of end-stage glioma spread.

Volume

83

Issue

6

First Page

504

Last Page

505

Share

COinS