Desmoplastic infantile ganglioglioma: A MAPK pathway-driven and microglia/macrophage-rich neuroepithelial tumor

Melissa M. Blessing, Patrick R. Blackburn, Chandra Krishnan, Virginia L. Harrod, Emily G.Barr Fritcher, Christopher D. Zysk, Rory A. Jackson, Dragana Milosevic, Asha A. Nair, Jaime I. Davila, Jessica R. Balcom, Robert B. Jenkins, Kevin Carl Halling, Benjamin R. Kipp, Amulya A.Nageswara Rao, Nadia N. Laack, David J. Daniels, William R. Macon, Cristiane M. Ida

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

MAPK pathway activation has been recurrently observed in desmoplastic infantile ganglioglioma/astrocytoma (DIG/DIA) with reported disproportionally low mutation allele frequencies relative to the apparent high tumor content, suggesting that MAPK pathway alterations may be subclonal. We sought to expand the number of molecularly profiled cases and investigate if tumor cell composition could account for the observed low mutation allele frequencies. Molecular (targeted neuro-oncology next-generation sequencing/RNA sequencing and OncoScan microarray) and immunohistochemical (CD68-PGM1/CD163/CD14/CD11c/lysozyme/CD3/CD20/CD34/ PD-L1) studies were performed in 7 DIG. Activating MAPK pathway alterations were identified in 4 (57%) cases: 3 had a BRAF mutation (V600E/V600D/V600-W604delinsDQTDG, at 8%-27% variant allele frequency) and 1 showed a TPM3-NRTK1 fusion. Copy number changes were infrequent and nonrecurrent. All tumors had at least 30% of cells morphologically and immunophenotypically consistent with microglial/macrophage lineage. Two subtotally resected tumors regrew; 1 was re-excised and received adjuvant treatment (chemotherapy/targeted therapy), with clinical response to targeted therapy only. Even with residual tumor, all patients are alive (median follow-up, 83 months; 19-139). This study further supports DIG as another MAPK pathway-driven neuroepithelial tumor, thus expanding potential treatment options for tumors not amenable to surgical cure, and suggests that DIG is a microglia/macrophage-rich neuroepithelial tumor with frequent low driver mutation allele frequencies.

Original languageEnglish (US)
Pages (from-to)1011-1021
Number of pages11
JournalJournal of Neuropathology and Experimental Neurology
Volume78
Issue number11
DOIs
StatePublished - Nov 1 2019

Keywords

  • BRAF
  • Desmoplastic infantile ganglioglioma (DIG)
  • Glioma
  • Molecular
  • NTRK
  • Pediatric
  • TPM3

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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  • Cite this

    Blessing, M. M., Blackburn, P. R., Krishnan, C., Harrod, V. L., Fritcher, E. G. B., Zysk, C. D., Jackson, R. A., Milosevic, D., Nair, A. A., Davila, J. I., Balcom, J. R., Jenkins, R. B., Halling, K. C., Kipp, B. R., Rao, A. A. N., Laack, N. N., Daniels, D. J., Macon, W. R., & Ida, C. M. (2019). Desmoplastic infantile ganglioglioma: A MAPK pathway-driven and microglia/macrophage-rich neuroepithelial tumor. Journal of Neuropathology and Experimental Neurology, 78(11), 1011-1021. https://doi.org/10.1093/jnen/nlz086