Concurrent Gliomas in Patients with Multiple Sclerosis

BackgroundConcurrent malignant brain tumors in patients with multiple sclerosis (MS) constitute a rare but paradigmatic phenomenon for studying neuroimmunological mechanisms from both molecular and clinical perspectives. MethodsA multicenter cohort of 26 patients diagnosed with both primary brain tumors and multiple sclerosis was studied for disease localization, tumor treatment-related MS activity, and molecular characteristics specific for diffuse glioma in MS patients. ResultsMS neither predisposes nor protects from the development of gliomas. Patients with glioblastoma WHO grade IV without IDH mutations had a longstanding history of MS, whereas patients diagnosed with IDH-mutant astrocytoma WHO grade II received multiple sclerosis diagnosis mostly at the same time or later. Concurrent MS was associated with a lesser extent of tumor resection and a worse prognosis in IDH-mutant glioma patients (PFS 32 vs. 64 months, p=0.0206). When assessing tumor-intrinsic differences no distinct subgroup-defining methylation pattern was identified in gliomas of MS patients compared to other glioma samples. However, differential methylation of immune-related genetic loci including human leukocyte antigen locus on 6p21 and interleukin locus on 5q31 was found in MS patients vs. matched non-MS patients. In line, inflammatory disease activity increased in 42% of multiple sclerosis patients after brain tumor radiotherapy suggesting a susceptibility of multiple sclerosis brain tissue to pro-inflammatory stimuli such as ionizing radiation. ConclusionsConcurrent low-grade gliomas should be considered in multiple sclerosis patients with slowly progressive, expansive T2/FLAIR lesions. Our findings of typically reduced extent of resection in MS patients and increased MS activity after radiation inform future treatment decisions. Key points- Disease history and sequence of diagnosis differ in MS patients with high-vs low-grade glioma - Gliomas of MS patients harbor subtle methylation changes in immune-related genetic regions - Brain tumor radiotherapy is followed by MS disease activity Importance of the studyImmune escape is a hallmark of diffuse glioma, while inflammation is the underlying mechanism of multiple sclerosis. These opposing mechanisms concur in patients that suffer in parallel from multiple sclerosis and glioma. This study is the first to investigate the tumor characteristics, tumor treatment responses and effect on multiple sclerosis activity of a cohort of patients with both diseases. The data warrant caution in the interpretation of suspicious lesions in imaging and suggests risk loci for the observed detrimental effects of radiation specific to MS patients.