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Significance of H3K27M Mutation in "Nonmidline" High-Grade Gliomas of Cerebral Hemispheres
Case Report
Significance of H3K27M Mutation in "Nonmidline" High-Grade Gliomas of Cerebral Hemispheres Giuseppe La Rocca1, Giovanni Sabatino1, Roberto Altieri2, Francesco Signorelli1, Luca Ricciardi1, Marco Gessi3, Giuseppe Maria Della Pepa1
Key words Diffuse midline glioma - Glioblastoma - H3K27M-m - High-grade glioma - Histone mutation -
Abbreviations and Acronyms CNS: Central nervous system HGG: High-grade glioma WHO: World Health Organization From the 1Institute of Neurosurgery, Catholic University of Rome, Rome; 2Institute of Neurosurgery, University of Turin, Turin; and 3Institute of Neuropathology, Catholic University of Rome, Rome, Italy To whom correspondence should be addressed: Giuseppe Maria Della Pepa, M.D. [E-mail: [email protected]; giuseppemaria. [email protected]] Citation: World Neurosurg. (2019) 131:174-176. https://doi.org/10.1016/j.wneu.2019.08.024 Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
INTRODUCTION "Diffuse midline glioma H3K27M-mutant" represents a well-defined pathologic entity since the 2016 World Health Organization Classification of Central Nervous System (CNS) Tumors with specific characteristics and, regardless of histologic grade, poor prognosis. It arises from the midline structures including the thalamus, brainstem, and spinal cord from a mutation in either the H3F3A or HIST1H3B genes, which encode the histone H3 variants H3.3 and H3.1.1 H3K27M-mutant glioma responds more poorly to treatment and is associated with worse clinical outcome than wild-type tumors. Mutation detection is now diagnostic for "diffused midline gliomas" and, along with the peculiar abovementioned midline localization, defines 2 specific characteristics of this pathologic entity. We herein present a case of butterfly high-grade glioma (HGG) harboring from
174
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- BACKGROUND:
"Diffuse midline glioma H3K27M-mutant" (a mutation gene encoding H3 histone variants) represents a defined pathologic entity since the 2016 World Health Organization Central Nervous System classification and includes midline structures, namely the thalamus, brainstem, and spinal cord. H3K27M-mutant glioma responds more poorly and is associated with worse clinical outcome. Mutation detection is now diagnostic for "diffused midline gliomas." We report on a case arising in an atypical nonmidline localization with an exceedingly adverse course. The present case raises the question of the possible meaning of the H3K27M-mutation in high-grade gliomas arising from the cerebral hemispheres and its implications from prognostic and therapeutic views.
- CASE
DESCRIPTION: A 48-year-old woman was admitted with a mass arising from the splenium of the corpus callosum with bilateral hemispheric extension, displaying magnetic resonance imaging characteristics typical of a high-grade glioma. Needle biopsy confirmed the diagnosis of "diffuse astrocytic neoplasm, World Health Organization grade IV." Immunostaining of the tumor revealed the H3K27M-mutant nuclear expression. The patient was referred to adjuvant therapy and died 3 months after biopsy.
- CONCLUSIONS:
This experience highlights the possible negative prognostic impact of H3K27M-m and possibility that H3K27M-m could be a reliable prognostic indicator to be considered in not only diffuse midline gliomas but also gliomas from the cerebral hemispheres. Because of the rarity and limited knowledge of this specific mutation in this experience, reports should be encouraged.
the splenium of the corpus callosum harboring the H3K27M mutations and discuss the significance of the H3K27M-m in HGG from prognostic and therapeutic views. CASE PRESENTATION A 48-year-old woman with history of partial left-side sensory seizures, headache, and increasing drowsiness was admitted to our department. Magnetic resonance imaging showed a mass arising from the splenium of the corpus callosum with bilateral extension, displaying magnetic resonance imaging characteristics typical of an HGG (Figure 1). The patient underwent a stereotactic needle biopsy; frozen section was
compatible with HGG. Postoperative computed tomography scan showed no procedural complication. Pathologic examination revealed a highly cellular astrocytic tumor with marked cell polymorphism. Vascular proliferations and mitoses were present (Figure 2A). The tumor was positive for glial fibrillary acidic protein and showed expression of H3K27M and loss of H3K27-3m (see Figure 2B). MIB1 index was assessed at 20%. P53 had an expression of 5% 10%. The tumor cells were negative for IDH1 (R132H) mutant protein and had normal ATRX expression. Pathologic final diagnosis was "diffuse astrocytic neoplasm, World Health Organization (WHO) grade IV."
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2019.08.024
CASE REPORT GIUSEPPE LA ROCCA ET AL.
Figure 1. Preoperative brain magnetic resonance imaging with gadolinium depicting a solid mass arising from the splenium of the corpus callosum
Immunostaining of the tumor for H3K27M-mutant protein established the presence of nuclear expression, combined with loss of histone H3 lysine 27 trimethylation. The patient was referred to adjuvant therapy. She died 3 months after surgery, before this manuscript was completed. At the time of biopsy, as for all patients harboring HGGs in our department, she signed a consent for the use of her clinical data for scientific purposes, in an anonymized form. DISCUSSION "Diffuse midline glioma, H3K27Mmutant" has been recently classified by the 2016 WHO revision of CNS tumors. Such tumors mostly arise in the CNS midline structures, especially in the pediatric population, and are correlated with a largely dreary prognosis. According to the discovery of histone 3 mutations in 2012, the scenario seems to be due to H3 lysine 27-to-methionine mutations in H3F3A or HIST1H3B/C, encoding for histone 3 variants H3.3 and H3.1, respectively, which are considered hallmark events driving gliomagenesis.2,3 The incidence of H3K27M-m in diffuse midline gliomas is associated with worse
with bilateral extension and enhancement after gadolinium.
overall survival compared with H3 wildtype ones, regardless of the histology.4 It is necessary to underline that those lesions are located in deep and critical midline structures, thus precluding a total/subtotal resection in the majority of the cases. It has not yet been clarified what the real impact of H3K27M-m is on prognosis, nor the mechanism's location or biological aspect of the mutation. Conversely, H3K27M-m seems to be an unusual alteration in peripherally or hemispheric diffuse brain gliomas. The latest literature reports that diffuse thalamic gliomas in adults harboring H3K27M mutation are not associated with a uniformly poor prognosis, and there are a few reports of circumscribed low-grade glial neoplasms centered in midline structures that harbor H3K27M mutation.5 Although H3K27M-mutant circumscribed gliomas show poor survival compared with H3-wild-type circumscribed gliomas, prognosis remains significantly better than both H3K27Mmutant and H3-wild-type diffused gliomas.2 In the present case the patient had a butterfly mass centered on the splenius of the corpus callosum and she was treated with adjuvant radiation and chemotherapy with temozolomide (as recommended) until death 3 months after surgery. This
WORLD NEUROSURGERY 131: 174-176, NOVEMBER 2019
Figure 2. Histopathology of the lesion. The neuropathologic examination of surgical specimens revealed a highly cellular astrocytic tumor with marked cell polymorphism. Vascular proliferations and mitoses were present. The tumor was glial fibrillary acidic protein positive and showed expression of H3K27M and loss of H3K27-3me. The tumor consisted of densely packed glial cells with marked nuclear polymorphism. Mitoses and vascular proliferations were present (A); the tumor showed nuclear positivity for H3K27M (B).
www.journals.elsevier.com/world-neurosurgery
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CASE REPORT GIUSEPPE LA ROCCA ET AL.
experience highlights the negative prognostic impact of H3K27M-m in diffuse midline gliomas and supports their inclusion in grade IV by the 2016 WHO, regardless of the histologic findings. An aspect that is surely peculiar is the localization of this tumor, along with the nondiffused aspect. From a phylogenetic point of view, corpus callosum fibers originate from the large pyramidal cells of the telencephalic cortex, often as collateral fibers; they are therefore commissural fibers coming from neocortical areas with a precise topographic organization, thus with a very different embryogenesis compared with proper midline structures such as talami, midbrain, and spinal cord. Notwithstanding that the corpus callosum is not proper a midline structure, the biological behavior of the lesion was aggressive and the prognosis in terms of survival was poor, as typically shown in midline H3K27M-m gliomas. CONCLUSIONS The case highlights the possibility that the H3K27M-m could be a reliable prognostic
176
www.SCIENCEDIRECT.com
indicator to be considered in not only diffuse midline gliomas but also HGGs. Because of the rarity and limited knowledge of this specific mutation in HGGs, other reports should be encouraged to understand the prognosis and best treatment options for the novel entity in both midline and nonmidline tumors that carry this fatal oncogenic mutation. Even if only the diffuse glioma localized in midline structures meets the definition of the entity "diffuse midline glioma, H3K27M-mutant," grade IV according to 2016 WHO classification, we believe that immunostaining for H3K27M-m protein should be taken into account also for IDHwildtype HGGs of the cerebral hemispheres; this alternative conceptualization should be addressed and discussed in larger series of patients to further evaluate mutation significance in this subset of tumors. REFERENCES 1. Lopez G, Oberheim Bush NA, Berger MS, Perry A, Solomon DA. Diffuse non-midline glioma with H3F3A K27M mutation: a prognostic and treatment dilemma. Acta Neuropathol Commun. 2017;5:38.
2. Pratt D, Natarajan SK, Banda A, et al. Circumscribed/non-diffuse histology confers a better prognosis in H3K27M-mutant gliomas. Acta Neuropathol. 2018;135:299-301. 3. Schwartzentruber J, Korshunov A, Liu XY, et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature. 2012;482:226-231. 4. Khuong-Quang DA, Buczkowicz P, Rakopoulos P, 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. 5. Feng J, Hao S, Pan C, et al. The H3.3 K27M mutation results in a poorer prognosis in brainstem gliomas than thalamic gliomas in adults. Hum Pathol. 2015;46:1626-1632.
Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received 15 May 2019; accepted 5 August 2019 Citation: World Neurosurg. (2019) 131:174-176. https://doi.org/10.1016/j.wneu.2019.08.024 Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2019.08.024
Significance of H3K27M Mutation in "Nonmidline" High-Grade Gliomas of Cerebral Hemispheres Giuseppe La Rocca1, Giovanni Sabatino1, Roberto Altieri2, Francesco Signorelli1, Luca Ricciardi1, Marco Gessi3, Giuseppe Maria Della Pepa1
Key words Diffuse midline glioma - Glioblastoma - H3K27M-m - High-grade glioma - Histone mutation -
Abbreviations and Acronyms CNS: Central nervous system HGG: High-grade glioma WHO: World Health Organization From the 1Institute of Neurosurgery, Catholic University of Rome, Rome; 2Institute of Neurosurgery, University of Turin, Turin; and 3Institute of Neuropathology, Catholic University of Rome, Rome, Italy To whom correspondence should be addressed: Giuseppe Maria Della Pepa, M.D. [E-mail: [email protected]; giuseppemaria. [email protected]] Citation: World Neurosurg. (2019) 131:174-176. https://doi.org/10.1016/j.wneu.2019.08.024 Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
INTRODUCTION "Diffuse midline glioma H3K27M-mutant" represents a well-defined pathologic entity since the 2016 World Health Organization Classification of Central Nervous System (CNS) Tumors with specific characteristics and, regardless of histologic grade, poor prognosis. It arises from the midline structures including the thalamus, brainstem, and spinal cord from a mutation in either the H3F3A or HIST1H3B genes, which encode the histone H3 variants H3.3 and H3.1.1 H3K27M-mutant glioma responds more poorly to treatment and is associated with worse clinical outcome than wild-type tumors. Mutation detection is now diagnostic for "diffused midline gliomas" and, along with the peculiar abovementioned midline localization, defines 2 specific characteristics of this pathologic entity. We herein present a case of butterfly high-grade glioma (HGG) harboring from
174
www.SCIENCEDIRECT.com
- BACKGROUND:
"Diffuse midline glioma H3K27M-mutant" (a mutation gene encoding H3 histone variants) represents a defined pathologic entity since the 2016 World Health Organization Central Nervous System classification and includes midline structures, namely the thalamus, brainstem, and spinal cord. H3K27M-mutant glioma responds more poorly and is associated with worse clinical outcome. Mutation detection is now diagnostic for "diffused midline gliomas." We report on a case arising in an atypical nonmidline localization with an exceedingly adverse course. The present case raises the question of the possible meaning of the H3K27M-mutation in high-grade gliomas arising from the cerebral hemispheres and its implications from prognostic and therapeutic views.
- CASE
DESCRIPTION: A 48-year-old woman was admitted with a mass arising from the splenium of the corpus callosum with bilateral hemispheric extension, displaying magnetic resonance imaging characteristics typical of a high-grade glioma. Needle biopsy confirmed the diagnosis of "diffuse astrocytic neoplasm, World Health Organization grade IV." Immunostaining of the tumor revealed the H3K27M-mutant nuclear expression. The patient was referred to adjuvant therapy and died 3 months after biopsy.
- CONCLUSIONS:
This experience highlights the possible negative prognostic impact of H3K27M-m and possibility that H3K27M-m could be a reliable prognostic indicator to be considered in not only diffuse midline gliomas but also gliomas from the cerebral hemispheres. Because of the rarity and limited knowledge of this specific mutation in this experience, reports should be encouraged.
the splenium of the corpus callosum harboring the H3K27M mutations and discuss the significance of the H3K27M-m in HGG from prognostic and therapeutic views. CASE PRESENTATION A 48-year-old woman with history of partial left-side sensory seizures, headache, and increasing drowsiness was admitted to our department. Magnetic resonance imaging showed a mass arising from the splenium of the corpus callosum with bilateral extension, displaying magnetic resonance imaging characteristics typical of an HGG (Figure 1). The patient underwent a stereotactic needle biopsy; frozen section was
compatible with HGG. Postoperative computed tomography scan showed no procedural complication. Pathologic examination revealed a highly cellular astrocytic tumor with marked cell polymorphism. Vascular proliferations and mitoses were present (Figure 2A). The tumor was positive for glial fibrillary acidic protein and showed expression of H3K27M and loss of H3K27-3m (see Figure 2B). MIB1 index was assessed at 20%. P53 had an expression of 5% 10%. The tumor cells were negative for IDH1 (R132H) mutant protein and had normal ATRX expression. Pathologic final diagnosis was "diffuse astrocytic neoplasm, World Health Organization (WHO) grade IV."
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2019.08.024
CASE REPORT GIUSEPPE LA ROCCA ET AL.
Figure 1. Preoperative brain magnetic resonance imaging with gadolinium depicting a solid mass arising from the splenium of the corpus callosum
Immunostaining of the tumor for H3K27M-mutant protein established the presence of nuclear expression, combined with loss of histone H3 lysine 27 trimethylation. The patient was referred to adjuvant therapy. She died 3 months after surgery, before this manuscript was completed. At the time of biopsy, as for all patients harboring HGGs in our department, she signed a consent for the use of her clinical data for scientific purposes, in an anonymized form. DISCUSSION "Diffuse midline glioma, H3K27Mmutant" has been recently classified by the 2016 WHO revision of CNS tumors. Such tumors mostly arise in the CNS midline structures, especially in the pediatric population, and are correlated with a largely dreary prognosis. According to the discovery of histone 3 mutations in 2012, the scenario seems to be due to H3 lysine 27-to-methionine mutations in H3F3A or HIST1H3B/C, encoding for histone 3 variants H3.3 and H3.1, respectively, which are considered hallmark events driving gliomagenesis.2,3 The incidence of H3K27M-m in diffuse midline gliomas is associated with worse
with bilateral extension and enhancement after gadolinium.
overall survival compared with H3 wildtype ones, regardless of the histology.4 It is necessary to underline that those lesions are located in deep and critical midline structures, thus precluding a total/subtotal resection in the majority of the cases. It has not yet been clarified what the real impact of H3K27M-m is on prognosis, nor the mechanism's location or biological aspect of the mutation. Conversely, H3K27M-m seems to be an unusual alteration in peripherally or hemispheric diffuse brain gliomas. The latest literature reports that diffuse thalamic gliomas in adults harboring H3K27M mutation are not associated with a uniformly poor prognosis, and there are a few reports of circumscribed low-grade glial neoplasms centered in midline structures that harbor H3K27M mutation.5 Although H3K27M-mutant circumscribed gliomas show poor survival compared with H3-wild-type circumscribed gliomas, prognosis remains significantly better than both H3K27Mmutant and H3-wild-type diffused gliomas.2 In the present case the patient had a butterfly mass centered on the splenius of the corpus callosum and she was treated with adjuvant radiation and chemotherapy with temozolomide (as recommended) until death 3 months after surgery. This
WORLD NEUROSURGERY 131: 174-176, NOVEMBER 2019
Figure 2. Histopathology of the lesion. The neuropathologic examination of surgical specimens revealed a highly cellular astrocytic tumor with marked cell polymorphism. Vascular proliferations and mitoses were present. The tumor was glial fibrillary acidic protein positive and showed expression of H3K27M and loss of H3K27-3me. The tumor consisted of densely packed glial cells with marked nuclear polymorphism. Mitoses and vascular proliferations were present (A); the tumor showed nuclear positivity for H3K27M (B).
www.journals.elsevier.com/world-neurosurgery
175
CASE REPORT GIUSEPPE LA ROCCA ET AL.
experience highlights the negative prognostic impact of H3K27M-m in diffuse midline gliomas and supports their inclusion in grade IV by the 2016 WHO, regardless of the histologic findings. An aspect that is surely peculiar is the localization of this tumor, along with the nondiffused aspect. From a phylogenetic point of view, corpus callosum fibers originate from the large pyramidal cells of the telencephalic cortex, often as collateral fibers; they are therefore commissural fibers coming from neocortical areas with a precise topographic organization, thus with a very different embryogenesis compared with proper midline structures such as talami, midbrain, and spinal cord. Notwithstanding that the corpus callosum is not proper a midline structure, the biological behavior of the lesion was aggressive and the prognosis in terms of survival was poor, as typically shown in midline H3K27M-m gliomas. CONCLUSIONS The case highlights the possibility that the H3K27M-m could be a reliable prognostic
176
www.SCIENCEDIRECT.com
indicator to be considered in not only diffuse midline gliomas but also HGGs. Because of the rarity and limited knowledge of this specific mutation in HGGs, other reports should be encouraged to understand the prognosis and best treatment options for the novel entity in both midline and nonmidline tumors that carry this fatal oncogenic mutation. Even if only the diffuse glioma localized in midline structures meets the definition of the entity "diffuse midline glioma, H3K27M-mutant," grade IV according to 2016 WHO classification, we believe that immunostaining for H3K27M-m protein should be taken into account also for IDHwildtype HGGs of the cerebral hemispheres; this alternative conceptualization should be addressed and discussed in larger series of patients to further evaluate mutation significance in this subset of tumors. REFERENCES 1. Lopez G, Oberheim Bush NA, Berger MS, Perry A, Solomon DA. Diffuse non-midline glioma with H3F3A K27M mutation: a prognostic and treatment dilemma. Acta Neuropathol Commun. 2017;5:38.
2. Pratt D, Natarajan SK, Banda A, et al. Circumscribed/non-diffuse histology confers a better prognosis in H3K27M-mutant gliomas. Acta Neuropathol. 2018;135:299-301. 3. Schwartzentruber J, Korshunov A, Liu XY, et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature. 2012;482:226-231. 4. Khuong-Quang DA, Buczkowicz P, Rakopoulos P, 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. 5. Feng J, Hao S, Pan C, et al. The H3.3 K27M mutation results in a poorer prognosis in brainstem gliomas than thalamic gliomas in adults. Hum Pathol. 2015;46:1626-1632.
Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received 15 May 2019; accepted 5 August 2019 Citation: World Neurosurg. (2019) 131:174-176. https://doi.org/10.1016/j.wneu.2019.08.024 Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2019.08.024