Clinical, radiological, and molecular insights into extracranial metastases from adult gliomas

Background Extracranial metastases from adult gliomas cause diagnostic and therapeutic challenges and are generally poorly investigated. The aim of this study was to provide clinical and molecular insights into glioma metastasis.Methods Our cohort comprised tumor tissue from 16 glioma patients with metastasis (14 glioblastomas and 2 lower-grade gliomas). Paired primary tumors, recurrences, and metastases were investigated by DNA sequencing, genome-wide DNA methylation profiling, RNA sequencing, immunohistochemistry, and MRI examinations.Results The metastases were distributed across the scalp/upper neck (8), lymph nodes (5), bone (2), and liver (1). Six out of 14 glioblastomas displayed significant sarcomatous differentiation, consistent with the otherwise rare histological subtype gliosarcoma. A majority of the scalp lesions were connected to an intracranial brain tumor via tumor extension through craniotomy burr holes, proposing that surgery is a contributing factor to tumor spread. Next-generation sequencing-based mutational analysis revealed that the true metastases originated from the primary tumors and not later recurrences. We observed tumor plasticity as the tumors progressed to metastasis, demonstrated by changes in epigenetic methylation classes and transcriptional subtypes. Despite different locations of metastases in the cohort, the immune cell composition in the tumor microenvironment remained overall stable during tumor progression.Conclusion Metastases from adult gliomas originate from the primary brain tumors and not later recurrences. While RNA sequencing and methylation profiling revealed tumor plasticity during progression to metastasis, the immune cell composition remained overall stable.