Abstract Glioblastoma multiforme (GBM) is locally aggressive, yet it metastasizes outside the central nervous system (CNS) in only 0.4% of cases. Little is known about what enables this subset of GBMs to survive outside the CNS, so we conducted a PRISMA-compliant systematic review of metastatic GBM wherein we reviewed 3579 search results and 1080 abstracts, ultimately analyzing data from 139 studies and 211 unique patients. Additionally, we analyzed four modern-day cases treated at our institution. In our patients, primary GBM lesions revealed consistent mutations in NF1, TERT, TP53, CDK4, and RB1/PTEN genes. Unique to the metastatic lesions were amplifications in integral cell-cycle regulating genes such as p53 and PDGFRA/KIT, as well as increased vimentin and Ki-67 expression. These data support the hypothesis that glial cells likely underwent mesenchymal-like mutations prior to extra-CNS involvement. How these cells reach the extra-axial environment is still under debate. In our systematic review, we found that metastases were discovered near previous surgical sites in at least 36.9% of cases, suggesting tumor seeding into the scalp during surgery may facilitate mesenchymal-type mutation in some cases. However, this is unlikely to be sole mechanism of spread as there are several reports of spread without surgery, and other hypothesized mechanisms include spontaneously circulating cells and glymphatics. Other sites of GBM metastasis included bone (47.9%), lung (25.6%), lymph nodes (25.1%), and liver (14.2%). On average, metastases were diagnosed 12.1 months after the most recent resection, and the mean survival from discovery was 5.7 months. In sum, there is strong evidence that GBMs acquire novel mutations to survive outside the CNS, are spread spontaneously or iatrogenically, and portend a poor prognosis once disseminated. Routine genetic and molecular characterization of both primary and metastatic GBMs and widespread reporting will help further characterize mechanisms of spread for this rare but deadly pathology.
Read full abstract