Glioma

CASE REPORT
Year
: 2019  |  Volume : 2  |  Issue : 1  |  Page : 55--59

Diffuse midline glioma, H3-K27M mutant: Awareness leads to identification


Sadhana Tiwari1, Ishita Pant1, Sujata Chaturvedi1, Gurbachan Singh2,  
1 Department of Pathology, Institute of Human Behaviour and Allied Sciences, Delhi, India
2 Department of Neurosurgery, Guru Teg Bahadur Hospital, Delhi, India

Correspondence Address:
Dr. Sadhana Tiwari
Department of Pathology, Institute of Human Behaviour and Allied Sciences, Dilshad Garden, Delhi - 110 095
India

Abstract

Midline astrocytic neoplasms have distinct molecular characteristics, quite different from astrocytic neoplasms with similar morphology but not located in the midline. It is imperative that neuropathologists should be aware of the existence of these tumors, so they can be correctly diagnosed. Here, we discuss the case of a 14-year-old boy who presented with acute onset of vomiting followed by loss of consciousness. Subsequent magnetic resonance imaging revealed an ill-defined exophytic lesion arising from the brainstem and extending into the left cerebellopontine angle, with areas of hemorrhage and patchy restricted diffusion. The tumor was resected. Microscopy revealed medium-sized tumor cells in diffuse sheets, having round nuclei, granular chromatin, and scant cytoplasm. Microvascular and endothelial cell proliferation in small necrotic areas were seen. Mitosis was 0–1 per high-power field. By routine histopathological analysis, all features were consistent with the diagnosis of glioblastoma. Tumor cells were immunopositive for glial fibrillary acidic protein and isocitrate dehydrogenase-1 mutation (R132H), immunonegative for p53, and retained alpha thalassemia/mental retardation syndrome X-linked. It also showed a strong immunopositivity for H3-K27M mutation. A diagnosis of a diffuse midline glioma with H3-K27M mutation corresponding to the World Health Organization Grade IV was made. This case highlights the importance of exploring signature mutations in well-defined tumor categories such as H3-K27M-mutant diffuse midline glioma.



How to cite this article:
Tiwari S, Pant I, Chaturvedi S, Singh G. Diffuse midline glioma, H3-K27M mutant: Awareness leads to identification.Glioma 2019;2:55-59


How to cite this URL:
Tiwari S, Pant I, Chaturvedi S, Singh G. Diffuse midline glioma, H3-K27M mutant: Awareness leads to identification. Glioma [serial online] 2019 [cited 2022 Aug 13 ];2:55-59
Available from: http://www.jglioma.com/text.asp?2019/2/1/55/255149


Full Text

 Introduction



Based on genetic alterations in addition to histopathologic features, the term “diffuse midline glioma,” a high-grade infiltrative astrocytoma arising from midline structures of the brain, is an added entity in the World Health Organization (WHO) Classification of Tumors of the Central Nervous System, 4th edition. Although it mainly occurs in children, adults can also develop the same disorder. This term includes a formerly referred entity, the diffuse intrinsic pontine glioma (DIPG). The H3K27 missense mutation occurs in two genes (H3F3A and HIST1H3B) encoding histone H3 variants, H3.3, and H3.1, respectively. The substitution of lysine for methionine at codon 27 (K27M) occurs in these two histone variants.[1] These aggressive tumors are classified as Grade IV regardless of histological features and exhibit poor prognosis. Herein, we emphasize the importance of correct subtyping of high-grade glioma for its appropriate prognostic and clinical significance and describe a case report of a pediatric diffuse midline glioma.

 Case Report



A 14-year-old boy presented with an acute onset of a single episode of vomiting followed by loss of consciousness. On examination, the patient had diplopia, nystagmus, and motor weakness. Subsequent magnetic resonance imaging (MRI) revealed an ill-defined exophytic lesion arising from pons and medulla and extending into the left cerebellopontine angle with areas of hemorrhage and patchy restricted diffusion [Figure 1]. The patient's father signed the written informed consent.{Figure 1}

Based on the clinicoradiologic findings, a provisional diagnosis of brainstem glioma was made. The patient underwent retromastoid craniotomy and tumor resection. The tumor was soft to firm in consistency, grayish-white in color, with mild-to-moderate vascularity.

Postoperatively, a very tiny specimen was sent for histopathological examination and was subjected to squash smears preparation that showed features of low-grade glioma. Afterward, the specimen received in formalin for paraffin sections was stained with hematoxylin and eosin, which revealed a cellular tumor composed of medium-sized cells in diffuse sheets, having round nuclei, granular chromatin, conspicuous nucleoli, and scant cytoplasm [Figure 2]. At places, perinuclear clearing along with microvascular and endothelial cell proliferation and small areas of necrosis was seen. Mitosis was 0–1/high-power field [Figure 2]. On routine histopathology, all features were consistent with the diagnosis of glioblastoma.{Figure 2}

Since WHO 2016 classification,[2] clearly defines a separate entity of diffuse midline glioma, we evaluated the tumor for the presence of the H3K27M-mutation. Immunohistochemical staining showed that the tumor cells were positive for glial fibrillary acidic protein, retained alpha thalassemia/mental retardation syndrome X-linked, and showed immunopositivity for isocitrate dehydrogenase-1 (IDH-1) mutation and immunonegativity for p53. More importantly, there was a strong immunopositivity for H3-K27M mutation [Figure 2]. The diagnosis of a diffuse midline glioma with H3-K27M mutation was made in accordance with the WHO Classification of Tumors of the Central Nervous System, 4th edition. In spite of the best postoperative care, the patient died 2 weeks postoperatively.

 Discussion



In the pediatric population, diffuse midline glioma arises from the pons (about 50%), thalamus (13%), cerebellum (5%), and spinal cord (3%).[3] According to the WHO Classification of Tumors of the Central Nervous System, 4th edition,[2] the median age of presentation of diffuse midline glioma is 5–11 years with the pontine tumors developing earlier (7 years) than the thalamic tumors (11 years). There is no sex difference.

Solomon et al.[1] and Aboian et al.[4] analyzed the data of 47 and 24 cases in their studies of diffuse midline glioma for histone H3-K27M-mutation, respectively. Solomon et al. found that the age at diagnosis ranged from 2 to 65 years (median 14 years) and concluded pontine tumors (median age 7 years) develop at an earlier age than thalamic (24 years) and spinal cord (25 years) tumors. The incidence with respect to location and age of these tumors is summarized in [Table 1] and [Figure 3].[1]{Table 1}{Figure 3}

The clinical presentation depends mainly on the location of the tumor, but the classic clinical presentation is the triad of multiple cranial neuropathies, long tract signs, and ataxia. The history is usually short and includes nausea, vomiting, drowsiness, up-beating nystagmus, or facial numbness. On MRI, these tumors are usually T1 hypointense and T2 hyperintense. These tumors can show contrast enhancement, necrosis, and/or hemorrhage. In 2017, Aboian et al.[4] reviewed imaging characteristics of these tumors in pediatric patients [Table 2]. They also tried to compare the imaging characteristics of H3-K27M mutant to wild-type tumor. For posterior fossa tumors, they found no significant difference and for thalamus location due to a lesser number of cases, the comparison was limited.{Table 2}

Tumors harboring H3-K27M mutation show wide morphological variations including small monomorphic cells, giant cells, epithelioid cells, primitive neuroectodermal tumor-like tumor foci, and prominent pilomyxoid features.[4]

For pediatric DIPG and nonbrainstem glioblastoma, two separate studies conducted in 2012, identified the somatic mutations of histone genes, H3F3A (75%) and HIST1H3B (20%–25%) encoding histone H3 variants H3.3 and H3.1, respectively. H3.3 and H3.1 mutations occur in a mutually exclusive manner.[5] Majority of DIPGs and thalamic glioblastoma showed recurrent lysine to methionine substitution at codon 27 (K27M) in one of the two histone H3 variants.[6] A recurrent glycine to arginine/valine substitution at codon 34 was identified in pediatric nonmidline glioblastomas arising from the cerebral hemispheres.[6] The presence of this distinct H3-K27M mutation imparts clinically aggressive behavior and worse prognosis regardless of the histological grade of the tumor and gives reason to keep it as Grade IV tumor by 2016 WHO. Almost ~30% of DIPGs show activating missense somatic mutations in ACVR1 G328 that are concurrent with HIST1H3B K27M mutation.[7] Some important mutation associations of these tumors[2],[8] are summarized in [Table 3] and [Table 4].{Table 3}{Table 4}

Multivariate analysis by Castel et al.[9] showed various prognostic factors such as ACVR1 mutation, histone H3 wildtype/K27M status, clinicoradiological risk score, metastasis, and MRI contrast enhancement, but the strongest predictor of survival was mutated histone H3.

These tumors can neither be completely removed surgically due to their location nor be treated effectively with radiotherapy or chemotherapy. In 2017, Piunti et al.[10] found significant suppression of tumor growth in DIPG patients treated with the epigenetic modifier, JQ1, a bromodomain, and terminal family protein inhibitor. Other new epigenetic strategies have been developed targeting chromatin-modifying enzymes. In addition, in some cases, nanotechnology has proven effective.[11] The recognition of this morphologically and molecularly defined tumors accounts for specific therapy against these mutations and their prognosis [Figure 4].[8]{Figure 4}

 Conclusion



The case highlights the importance of exploring for signature mutations in well-defined tumor categories like H3-K27M-mutant diffuse midline gliomas. Phenotypically similar tumors may be genetically heterogeneous and, therefore, have different biological behavior entities.

Financial support and sponsorship

Nil.

Institutional review board statement

We have only diagnosed this case. It does not involve any kind of research activity or clinical trial. So it is exempted.

Conflicts of interest

There are no conflicts of interest.

Declaration of patient consent

The authors certify that they have obtained the appropriate patient consent form. In the form, the patient's father has given his consent for the patient's images and other clinical information to be reported in the journal. The patient's father understands that the patient's name and initial will not be published and due efforts will be made to conceal his identity.

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