Systemic metastasis in glioblastoma may represent the emergence of neoplastic subclones

Glioblastomas only rarely metastasize to sites outside the central nervous system, for reasons that are poorly understood. We report the clinicopathol ogical and molecular genetic findings in 6 patients with metastatic gliobla stoma. Four patients were under the age of 32 and all but 1 patient died wi thin 2 yr of diagnosis. The number of metastases ranged from 1 to 3. At the time of death, 3 patients had apparent tumor control at their primary site . We evaluated DNA from both primary and metastatic glioblastomas for genet ic alterations commonly found in glioblastomas: TP53 mutations, CDKN2A/p16 deletions, EGFR amplification, and allelic loss of chromosomes 1p, 10q and 19q. Four of 6 cases had TP53 mutations and only single cases had EGFR ampl ification, CDKN2A/p16 deletions, or allelic loss of 1p, 10q and 19q; 2 case s had no detectable genetic alterations. In 2 cases, the primary and metast atic tumors had identical genotypes. Remarkably, however, 2 cases had diffe rent TP53 alterations in the primary and metastatic lesions, or among the m etastatic tumors, which suggests that some metastatic deposits may represen t emergence of subclones that were not necessarily dominant in the primary tumor. The present observations and a review of the recent literature demon strate that metastatic glioblastomas tend to occur in younger adults who do not follow long clinical courses, and may be characterized by TP53 mutatio ns and differential clonal selection.