Very Late Recurrence of Glioblastoma after 8 Years of Progression-Free Survival: A Case Report and Review of Tumor Dormancy

Technical Summary: Very Late Recurrence of Glioblastoma after 8 Years of Progression-Free Survival

Problem Statement
Glioblastoma (GBM), a WHO grade 4 diffuse glioma, is characterized by aggressive behavior and early recurrence, typically within 6–10 months of diagnosis, despite maximal safe resection and standard chemoradiation (Stupp protocol). Long-term survival beyond three years is rare (<5%), and progression-free survival (PFS) exceeding five years is estimated at less than 2–3%. A specific clinical challenge arises in long-term survivors: distinguishing between true, very late tumor recurrence and delayed treatment-related effects, such as radiation necrosis. While tumor dormancy is a hypothesized mechanism for such rare, prolonged remissions, documented cases of recurrence after eight years—particularly in patients treated with radiotherapy alone without temozolomide—are exceedingly scarce in the literature.

Methodology
This study presents a single case report of a middle-aged male patient initially diagnosed in 2017 and a review of relevant literature regarding long-term GBM survival and dormancy.

• Initial Treatment (2017): The patient underwent gross total resection of a supratentorial glioblastoma followed by adjuvant external beam radiotherapy (45 Gy in 25 fractions). No chemotherapy (temozolomide) was administered due to financial constraints and limited availability at the time.
• Surveillance: The patient was monitored via serial clinical evaluations and MRI scans every 6–12 months for the first five years, and annually thereafter.
• Recurrence Evaluation (November 2025): Upon presentation with progressive headaches and memory impairment eight years post-initial therapy, the patient underwent multimodal neuroimaging, including contrast-enhanced MRI and multivoxel MR spectroscopy (MRS).
• Histopathological Confirmation: A repeat biopsy was performed to confirm the nature of the lesion. Immunohistochemistry and molecular profiling (IDH, ATRX, Ki-67) were conducted on the recurrent tissue.

Key Results

• Clinical Course: The patient maintained a clinically stable, symptom-free state for nearly eight years following initial surgery and radiotherapy.
• Imaging Findings: MRI revealed a large (7.3 × 5.3 × 6.4 cm), heterogeneously enhancing, necrotic mass in the left frontotemporal region involving the basal ganglia, thalamus, and corpus callosum. Key features included extensive vasogenic edema and patchy diffusion restriction.
• MR Spectroscopy: Multivoxel MRS demonstrated a metabolite profile strongly indicative of high-grade neoplasm rather than radiation necrosis. Specifically, the Cho/Cr ratio was markedly elevated (up to 4.5), and N-acetylaspartate (NAA) was severely suppressed (NAA/Cho ~0.109–0.227).
• Histopathology: The recurrent biopsy confirmed anaplastic, hypercellular glial tumor with pleomorphic astrocytic cells, brisk mitotic activity, microvascular proliferation, and focal necrosis.
  • Immunohistochemistry: GFAP positive; Ki-67 proliferative index 20–30%; IDH negative; ATRX loss of expression.
  • Diagnosis: Recurrent IDH-wildtype glioblastoma.

Key Contributions

• Documentation of Extreme PFS: This report details an unusually prolonged progression-free survival of eight years in an IDH-wildtype glioblastoma patient treated with surgery and radiotherapy alone, a scenario rarely reported in contemporary series.
• Differentiation of Recurrence vs. Necrosis: The case illustrates the critical utility of advanced imaging, specifically MR spectroscopy, in resolving diagnostic ambiguity between true late recurrence and radiation-induced injury in long-term survivors. The elevated Cho/Cr ratio provided definitive evidence of neoplastic recurrence.
• Evidence for Tumor Dormancy: The clinical trajectory supports the biological concept of tumor dormancy, where residual cells may remain in a non-proliferative state for years before re-emerging, challenging the paradigm of GBM as invariably a rapidly lethal malignancy.

Significance and Claims
The authors assert that this case highlights the profound biological heterogeneity of glioblastoma. While the absence of initial molecular profiling (e.g., MGMT status) limits a complete characterization of the baseline biology, the extended remission suggests a potentially favorable intrinsic tumor phenotype. The paper concludes that:

1. Long-term surveillance is warranted: Even after prolonged remission, survivors of GBM require continued monitoring, as very late recurrence is possible.
2. Contemporary tissue sampling is essential: Upon recurrence, modern tissue sampling with molecular profiling is necessary to guide salvage management and trial selection, as the biology of the recurrent tumor may differ from the initial presentation.
3. Reframing GBM Biology: The existence of such cases suggests that for a biologically selected subset of patients, GBM may behave as a potentially dormant rather than uniformly aggressive disease.

The authors maintain a modest stance, acknowledging that while this case is an outlier, it does not fundamentally alter the standard prognosis for the majority of GBM patients but rather emphasizes the need for individualized long-term management and further investigation into the mechanisms of tumor dormancy.