Incidence and clinicopathologic features of H3 K27M mutations in adults with radiographically-determined midline gliomas

doi:10.1007/s11060-019-03134-x

. 2019 May;143(1):87-93.

doi: 10.1007/s11060-019-03134-x. Epub 2019 Mar 12.

Incidence and clinicopathologic features of H3 K27M mutations in adults with radiographically-determined midline gliomas

Karisa C Schreck^{1

2

3}, Surabhi Ranjan^{1

3}, Nebojša Skorupan^{1

3}, Chetan Bettegowda^{1

3

4}, Charles G Eberhart^{3

5}, Heather M Ames^{5

6}, Matthias Holdhoff^{7

8}

Affiliations

¹ Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 201 North Broadway, Viragh Building, 9th floor, Post Box 3, Baltimore, MD, 21287, USA.
² Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³ Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁶ Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA.
⁷ Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 201 North Broadway, Viragh Building, 9th floor, Post Box 3, Baltimore, MD, 21287, USA. mholdho1@jhmi.edu.
⁸ Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. mholdho1@jhmi.edu.

PMID: 30864101
PMCID: PMC6482123
DOI: 10.1007/s11060-019-03134-x

Incidence and clinicopathologic features of H3 K27M mutations in adults with radiographically-determined midline gliomas

Karisa C Schreck et al. J Neurooncol. 2019 May.

. 2019 May;143(1):87-93.

doi: 10.1007/s11060-019-03134-x. Epub 2019 Mar 12.

Authors

Karisa C Schreck^{1

2

3}, Surabhi Ranjan^{1

3}, Nebojša Skorupan^{1

3}, Chetan Bettegowda^{1

3

4}, Charles G Eberhart^{3

5}, Heather M Ames^{5

6}, Matthias Holdhoff^{7

8}

Affiliations

¹ Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 201 North Broadway, Viragh Building, 9th floor, Post Box 3, Baltimore, MD, 21287, USA.
² Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³ Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁶ Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA.
⁷ Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 201 North Broadway, Viragh Building, 9th floor, Post Box 3, Baltimore, MD, 21287, USA. mholdho1@jhmi.edu.
⁸ Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. mholdho1@jhmi.edu.

PMID: 30864101
PMCID: PMC6482123
DOI: 10.1007/s11060-019-03134-x

Abstract

Purpose: H3 K27 mutations, most commonly in H3F3A, are common in diffuse midline glioma. The exact frequency of these mutations in adults with gliomas in the midline location is unknown. This study was conducted to define the incidence of H3 K27M mutations in this location and to compare clinicopathological features with those of patients who do not harbor this mutation.

Methods: Consecutive glioma cases from 2007 to 2017 were screened for gliomas in the midline location. Immunohistochemistry was performed on all available tissue for mutations of H3 K27M, IDH1, and ARTX.

Results: Of 850 gliomas screened, 163 cases had midline glioma on MRI. Sufficient FFPE tissue was available for 123 cases (75%). H3 K27M mutation was identified in 18 of 123 cases (15%). All except one H3 K27M-mutant tumors were WHO grade III or IV on histology, while non-mutant tumors encompassed all four grades. The most common midline locations for H3 K27M-mutated tumors were midbrain (2/3; 67%), pons (4/11; 36%), and cerebellum (6/24; 25%). As compared to H3 K27M-wildtype tumors, there were no differences in age at diagnosis, sex, tumor grade, contrast enhancement on MRI, extent of resection, or treatment received. In this cohort, median survival was longer for patients with H3 K27M-mutated tumors (n = 18; 17.6 months) compared with high-grade wildtype tumors (n = 74; 7.7 months, p = 0.03).

Conclusions: H3 K27M mutations are common in midline gliomas in adults and can present in all midline locations. Survival comparison between H3 K27M-mutant and wildtype midline gliomas suggests that survival may be similar or possibly improved if the mutation is present.

Keywords: Diffuse midline glioma; Glioma; H3 K27M; IDH1.

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Conflict of interest statement

The authors have no conflict of interest related to this manuscript. M.H. served on an advisory board of Celgene, Abbvie and BTG International Inc.

Figures

**Fig. 1**
a Hematoxilin and eosin stain showing both normal and neoplastic cells, and b H3 K27M immunostain showing positive neoplastic nuclei (brown); c Clinical and histopathologic features of adults with H3 K27M gliomas (N = 18)

**Fig. 2**
Overall survival of H3 K27M-mutated patients compared with a all wildtype patients (p = 0.32) or b Grade III or IV wildtype patients only (p = 0.031). Median survival was 17.6 months for H3 K27M-mutated, 11.3 months for all H3 K27M-non-mutant, and 7.7 months for non-mutant grade III or IV midline gliomas

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References

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[1] Wu G, Broniscer A, McEachron TA, Lu C, Paugh BS, Becksfort J, Qu C, Ding L, Huether R, Parker M, et al. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet. 2012;44:251–253. doi: 10.1038/ng.1102. - DOI - PMC - PubMed

[2] Wu G, Broniscer A, McEachron TA, Lu C, Paugh BS, Becksfort J, Qu C, Ding L, Huether R, Parker M, et al. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet. 2012;44:251–253. doi: 10.1038/ng.1102. - DOI - PMC - PubMed

[3] Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW. The 2016 world health organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131:803–820. doi: 10.1007/s00401-016-1545-1. - DOI - PubMed

[4] Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW. The 2016 world health organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131:803–820. doi: 10.1007/s00401-016-1545-1. - DOI - PubMed

[5] Khuong-Quang DA, Buczkowicz P, Rakopoulos P, Liu XY, Fontebasso AM, Bouffet E, Bartels U, Albrecht S, Schwartzentruber J, Letourneau L, et al. K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol. 2012;124:439–447. doi: 10.1007/s00401-012-0998-0. - DOI - PMC - PubMed

[6] Khuong-Quang DA, Buczkowicz P, Rakopoulos P, Liu XY, Fontebasso AM, Bouffet E, Bartels U, Albrecht S, Schwartzentruber J, Letourneau L, et al. K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol. 2012;124:439–447. doi: 10.1007/s00401-012-0998-0. - DOI - PMC - PubMed

[7] Buczkowicz P, Bartels U, Bouffet E, Becher O, Hawkins C. Histopathological spectrum of paediatric diffuse intrinsic pontine glioma: diagnostic and therapeutic implications. Acta Neuropathol. 2014;128:573–581. doi: 10.1007/s00401-014-1319-6. - DOI - PMC - PubMed

[8] Buczkowicz P, Bartels U, Bouffet E, Becher O, Hawkins C. Histopathological spectrum of paediatric diffuse intrinsic pontine glioma: diagnostic and therapeutic implications. Acta Neuropathol. 2014;128:573–581. doi: 10.1007/s00401-014-1319-6. - DOI - PMC - PubMed

[9] Louis DN, Giannini C, Capper D, Paulus W, Figarella-Branger D, Lopes MB, Batchelor TT, Cairncross JG, van den Bent M, Wick W, et al. cIMPACT-NOW update 2: diagnostic clarifications for diffuse midline glioma, H3 K27M-mutant and diffuse astrocytoma/anaplastic astrocytoma, IDH-mutant. Acta Neuropathol. 2018;135:639–642. doi: 10.1007/s00401-018-1826-y. - DOI - PubMed

[10] Louis DN, Giannini C, Capper D, Paulus W, Figarella-Branger D, Lopes MB, Batchelor TT, Cairncross JG, van den Bent M, Wick W, et al. cIMPACT-NOW update 2: diagnostic clarifications for diffuse midline glioma, H3 K27M-mutant and diffuse astrocytoma/anaplastic astrocytoma, IDH-mutant. Acta Neuropathol. 2018;135:639–642. doi: 10.1007/s00401-018-1826-y. - DOI - PubMed

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Incidence and clinicopathologic features of H3 K27M mutations in adults with radiographically-determined midline gliomas

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Incidence and clinicopathologic features of H3 K27M mutations in adults with radiographically-determined midline gliomas

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