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The early infiltrative phase of GBM hypothesis: are molecular glioblastomas histological glioblastomas in the making? A preliminary multicenter study

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Abstract

Purpose

The presence of necrosis or microvascular proliferation was previously the hallmark for glioblastoma (GBM) diagnosis. The 2021 WHO classification now considers IDH-wildtype diffuse astrocytic tumors without the histological features of glioblastoma (that would have otherwise been classified as grade 2 or 3) as molecular GBM (molGBM) if they harbor any of the following molecular abnormalities: TERT promoter mutation, EGFR amplification, or chromosomal + 7/−10 copy changes. We hypothesize that these tumors are early histological GBM and will eventually develop the classic histological features.

Methods

Medical records from 65 consecutive patients diagnosed with molGBM at three tertiary-care centers from our institution were retrospectively reviewed from November 2017-October 2021. Only patients who underwent reoperation for tumor recurrence and whose tissue at initial diagnosis and recurrence was available were included in this study. The detailed clinical, histopathological, and radiographic scenarios are presented.

Results

Five patients were included in our final cohort. Three (60%) patients underwent reoperation for recurrence in the primary site and 2 (40%) underwent reoperation for distal recurrence. Microvascular proliferation and pseudopalisading necrosis were absent at initial diagnosis but present at recurrence in 4 (80%) patients. Radiographically, all tumors showed contrast enhancement, however none of them showed the classic radiographic features of GBM at initial diagnosis.

Conclusions

In this manuscript we present preliminary data for a hypothesis that molGBMs are early histological GBMs diagnosed early in their natural history of disease and will eventually develop necrosis and microvascular proliferation. Further correlative studies are needed in support of this hypothesis.

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Data availability

Data obtained and analyzed in this manuscript is patient confidential. However, non-identified data is available from the corresponding author upon reasonable request.

Abbreviations

 + 7/−10:

Combined gain of chromosome 7 and loss of chromosome 10

cIMPACT-NOW:

Consortium to inform molecular and practical approaches to CNS tumor taxonomy

EGFR:

Epidermal growth factor receptor

GBM:

Glioblastoma

IDH:

Isocitrate DEHYDROGENASE

KPS:

Karnofsky performance score

MGMT:

O6-methylguanine-DNA-methyltransferase

molGBM:

Molecular glioblastoma

OS:

Overall survival

PFS:

Progression-free survival

TERT:

Telomerase Reverse transcriptase

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Funding

AQH was supported by the Mayo Clinic Professorship and a Clinician Investigator award, and Florida State Department of Health Research Grant, and the Mayo Clinic Graduate School, as well as the NIH (R43CA221490, R01CA200399, R01CA195503, and R01CA216855). SHK was supported by the FDA (R01 FD-R-07288). EHM receives unrelated research support from Boston Scientific Corp. and Varian Medical Systems, Inc.

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Authors and Affiliations

  1. Department of Neurosurgery, Mayo Clinic Florida, 4500 San Pablo Rd S, Jacksonville, FL, 32224, USA

    Andres Ramos-Fresnedo, Ricardo A. Domingo, Carlos Perez-Vega, Michael W. Pullen, Oluwaseun O. Akinduro, Joao P. Almeida, Kaisorn L. Chaichana & Alfredo Quiñones-Hinojosa

  2. Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, FL, USA

    Mark E. Jentoft

  3. Department of Neurosurgery, Mayo Clinic, Phoenix, AZ, USA

    Bernard R. Bendok

  4. Department of Radiation Oncology, Mayo Clinic, Jacksonville, FL, USA

    Daniel M. Trifiletti

  5. Department of Neurosurgery, Mayo Clinic, Rochester, MN, USA

    Terence C. Burns

  6. Department of Neurology, Mayo Clinic, Phoenix, AZ, USA

    Alyx B. Porter

  7. Department of Oncology, Mayo Clinic, Rochester, MN, USA

    Sani H. Kizilbash

  8. Department of Radiology, Mayo Clinic, Jacksonville, FL, USA

    Erik H. Middlebrooks

  9. Division Chair, Neuro-Oncology, Department of Neurology, Mayo Clinic, Florida, 4500 San Pablo Rd. S, Jacksonville, FL, 32224, USA

    Wendy J. Sherman

Authors
  1. Andres Ramos-Fresnedo
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  2. Ricardo A. Domingo
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  6. Joao P. Almeida
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  9. Kaisorn L. Chaichana
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  10. Daniel M. Trifiletti
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  11. Terence C. Burns
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  14. Erik H. Middlebrooks
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  15. Alfredo Quiñones-Hinojosa
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Contributions

Conceptualization: ARF, MWP, CPV, RAD, OOA, JPA, EHM, WJS. Methodology: ARF, MWP, CPV, RAD, OOA, JPA, DMT, ABP, TCB, SHK, EHM, WJS. Software: ARF, MWP. Validation: ARF, MWP. Formal analysis: ARF. Investigation: ARF, MWP, CPV, RAD, OOA, JPA. Resources: MEJ, BRB, DMT, KLC, ABP, AQH, TCB, SHK, EHM, WJS. Data Curation: ARF, MWP, CPV, RAD, OOA, JPA. Writing—original draft: ARF, MWP, CPV, RAD, OOA, JPA. Writing—review and editing: ARF, MWP, CPV, RAD, OOA, JPA, MEJ, BRB, DMT, KLC, ABP, AQH, TCB, SHK, EHM, WJS. Visualization: ARF, MWP, CPV, RAD, OOA, JPA, MEJ, BRB, DMT, KLC, ABP, AQH, TCB, SHK, EHM, WJS. Supervision: AQH, EHM, WJS. Project administration: EHM, WJS. Funding acquisition: AQH, EHM, WJS.

Corresponding authors

Correspondence to Alfredo Quiñones-Hinojosa or Wendy J. Sherman.

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Conflict of interest

EHM serves on an advisory board and receives consulting fees from Boston Scientific Corp. All other authors have no conflict of interest to disclose. The authors declare no competing interests.

Ethical approval

This study was approved by the institutional IRB.

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Written informed consent was obtained from all patients involved in this study.

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Ramos-Fresnedo, A., Domingo, R.A., Perez-Vega, C. et al. The early infiltrative phase of GBM hypothesis: are molecular glioblastomas histological glioblastomas in the making? A preliminary multicenter study. J Neurooncol 158, 497–506 (2022). https://doi.org/10.1007/s11060-022-04040-5

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