A Case of Multicentric Isocitrate Dehydrogenase-Wildtype Glioblastoma With Divergent Clonal Evolution

Here, we present a rare case of multicentric glioblastoma in which two spatially distinct tumors exhibited different molecular profiles. A 56-year-old woman presented with progressive headache and speech difficulties. Magnetic resonance imaging (MRI) of the brain revealed two separate contrast-enhancing lesions, one in the left superior temporal gyrus and the other in the right middle temporal gyrus, with no connecting tract or edema on fluid-attenuated inversion recovery (FLAIR) imaging. Multicentric glioblastoma was suspected, and the patient underwent two-stage surgical resection of both tumors to achieve gross total removal. Histopathology confirmed both lesions as isocitrate dehydrogenase (IDH)-wildtype glioblastoma (World Health Organization (WHO) Grade 4), with typical features including extensive necrosis and microvascular proliferation. However, targeted next-generation sequencing revealed distinct genetic alterations in the two tumors. The left temporal lobe lesion harbored TERT promoter (TERTp) and BRAF p.Val600Glu (V600E) mutations. In contrast, the right temporal lobe lesion harbored a TERTp mutation, epidermal growth factor receptor (EGFR) amplification, MDM4 amplification, and a homozygous deletion of CDKN2A/B. The patient underwent standard postoperative chemoradiotherapy. One year after surgery, the right tumor recurred, whereas no recurrence was observed in the left temporal lobe. The BRAF p.Val600Glu (V600E) mutation in the left-sided tumor is a potential target for molecular therapy and may have contributed to the lack of recurrence. Multicentric glioblastomas are extremely rare, and only a few cases have been genetically profiled to date. Notably, most reported multicentric glioblastomas exhibit monoclonal driver mutations across lesions, suggesting a single origin. In the present case, the two tumors had different molecular signatures. This case underscores the importance of comprehensive genetic analysis of multicentric glioblastomas and highlights how divergent molecular pathologies can inform the prognosis and open opportunities for targeted treatment.