Glioblastoma, IDH-wildtype, is an aggressive primary brain tumor typically characterized by rapid progression and early neurologic symptoms. However, a subset of patients may harbor long-standing, pre-symptomatic disease detectable years before clinical manifestation and include low-grade histologic/radiographic features at diagnosis – molecular glioblastoma. The natural history of these cases remains poorly defined. Characterizing them may reveal biological or patient-related factors that influence tumor evolution and identify opportunities for early detection or intervention.

Patient 1: A 51-year-old female reported a several-year history of short-term memory issues and amnestic word-finding difficulty. Brain magnetic resonance imaging (MRI) obtained for unrelated sensory changes revealed a left hippocampal lesion, which she was unaware of.  Follow-up imaging two years later demonstrated stability but given concern for glioma and new symptoms the patient underwent hippocampal biopsy. Final pathology confirmed a diagnosis of glioblastoma, IDH wild-type (+7/-10, TERT promoter mutation, EGFR alteration, MGMT promoter unmethylated), despite lack of high-grade histologic features.

Patient 2: A 61-year-old female presented initially for headaches and ear pain and was found to have a left temporoparietal mass that remained radiographically stable for five years. Twelve years later, she developed focal seizures with confusion and visual symptoms. MRI demonstrated progression and resection confirmed molecular glioblastoma, IDH wildtype (+7/-10, TERT promoter mutation, MGMT promoter methylated), although histologically consistent with grade 3 astrocytoma. Overall survival was 4.7 years from time of diagnosis and 16.5 years from radiographic identification.

The described cases demonstrate that glioblastoma may have a prolonged or indolent state in some patients, contrary to the traditional notion of immediate and aggressive clinical evolution. Further study may reveal specific molecular or patient-related factors contributing to presentation and improve understanding of glioblastoma initiation, latency, and potential windows for early intervention.