Fulminant hemorrhagic course of a thalamic H3 K27-altered diffuse midline glioma in an adult patient: illustrative case

Nicolas Poletti Departments of Neurosurgery and

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Luca Lee Marques Departments of Neurosurgery and

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Nikolaus Deigendesch Pathology, University Hospital Basel, Basel, Switzerland; and

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Jehuda Soleman Departments of Neurosurgery and
Faculty of Medicine, University of Basel, Basel, Switzerland

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Luigi Mariani Departments of Neurosurgery and
Faculty of Medicine, University of Basel, Basel, Switzerland

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Raphael Guzman Departments of Neurosurgery and
Faculty of Medicine, University of Basel, Basel, Switzerland

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Jonathan Rychen Departments of Neurosurgery and

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BACKGROUND

H3 K27-altered diffuse midline gliomas (DMGs) are rare tumors, which are, regardless of their histological appearance, classified as World Health Organization grade 4 tumors. They are characterized by a diffuse growth pattern, midline anatomical location, and poor prognosis. Although DMGs occur predominantly in childhood, these tumors can also be found in young adults.

OBSERVATIONS

The authors present a case of a 29-year-old patient who was found unconscious with a Glasgow Coma Scale score of 4, along with abnormal extensor movements and bilateral middilated nonreactive pupils. Computed tomography revealed obstructive hydrocephalus due to an acute hemorrhage in a right thalamic lesion. To drain the hydrocephalus and relieve the ongoing central herniation, emergent placement of a right-sided, and later a left-sided, extraventricular drain was performed. Despite the postoperative resolution of hydrocephalus, the patient died shortly after because of the central brain herniation that had occurred. Brain autopsy revealed a H3 K27-altered DMG in the right thalamus.

LESSONS

Although typically described in the pediatric population and located in the pons, H3 K27-altered DMG should also be considered in young adult patients with midline lesions, particularly if they are located in the thalamus or brainstem. In rare cases, H3 K27-altered DMG may present with an acute tumor-related hemorrhage, leading to a fulminant clinical course.

ABBREVIATIONS

CT = computed tomography; DMG = diffuse midline glioma; EVD = external ventricular drain; GCS = Glasgow Coma Scale; MRI = magnetic resonance imaging; PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses; WHO = World Health Organization

BACKGROUND

H3 K27-altered diffuse midline gliomas (DMGs) are rare tumors, which are, regardless of their histological appearance, classified as World Health Organization grade 4 tumors. They are characterized by a diffuse growth pattern, midline anatomical location, and poor prognosis. Although DMGs occur predominantly in childhood, these tumors can also be found in young adults.

OBSERVATIONS

The authors present a case of a 29-year-old patient who was found unconscious with a Glasgow Coma Scale score of 4, along with abnormal extensor movements and bilateral middilated nonreactive pupils. Computed tomography revealed obstructive hydrocephalus due to an acute hemorrhage in a right thalamic lesion. To drain the hydrocephalus and relieve the ongoing central herniation, emergent placement of a right-sided, and later a left-sided, extraventricular drain was performed. Despite the postoperative resolution of hydrocephalus, the patient died shortly after because of the central brain herniation that had occurred. Brain autopsy revealed a H3 K27-altered DMG in the right thalamus.

LESSONS

Although typically described in the pediatric population and located in the pons, H3 K27-altered DMG should also be considered in young adult patients with midline lesions, particularly if they are located in the thalamus or brainstem. In rare cases, H3 K27-altered DMG may present with an acute tumor-related hemorrhage, leading to a fulminant clinical course.

ABBREVIATIONS

CT = computed tomography; DMG = diffuse midline glioma; EVD = external ventricular drain; GCS = Glasgow Coma Scale; MRI = magnetic resonance imaging; PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses; WHO = World Health Organization

With its publication in 2016, the fourth edition of the World Health Organization (WHO) Classification of Tumors of the Central Nervous System added histone H3 K27M–mutant diffuse midline glioma (DMG) as a new tumor entity, recognizing the central role of molecular diagnosis.1 With the update of the classification system in 2021, the nomenclature has been changed from H3 K27M–mutant to H3 K27–altered DMG to acknowledge the multiple mechanisms by which the epigenetic pathway can be affected.2 H3 K27–altered DMGs are a group of histologically heterogeneous tumors, which are, regardless of their histological appearance, classified as WHO grade 4 tumors.2 They are characterized by a diffuse growth pattern, midline anatomical location, and poor prognosis. Although DMGs occur predominantly in childhood and are listed in the pediatric diffuse high-grade gliomas group in the current WHO classification,2 these lesions can also be found in young adults.3 The most common tumor location in children is the brainstem, particularly the pons. In contrast, adult DMGs typically arise from the thalamus.3 The aim of this report is to present a rare case of an adult patient with a thalamic H3 K27–altered DMG who underwent a fulminant clinical course because of an acute tumor-related hemorrhage. We also aim to place this case into the context of the existing literature, which was systematically reviewed.

Illustrative Case

A 29-year-old male patient was brought intubated to the emergency department after being found unconscious at home with a Glasgow Coma Scale (GCS) score of 4 for an unknown period of time. The patient’s past medical history was unremarkable. Upon arrival at the hospital, his comatose state persisted at GCS score 4 (unsedated) with abnormal extensor movements and isochoric middilated pupils that were nonreactive to light bilaterally. Computed tomography (CT) showed a large right-sided thalamic hemorrhage (49 × 39 × 39 mm) with occlusion of the foramen of Monro and consecutive hydrocephalus (Fig. 1A, B). On the basis of these imaging findings, a tumor-related hemorrhage was suspected. To drain the acute hydrocephalus and relieve the ongoing central herniation, a right frontal ventriculostomy was immediately performed. Shortly after the procedure, the patient had a mydriatic pupil on the left side. Follow-up CT showed a correctly placed external ventricular drain (EVD) in the right frontal horn but entrapment of the left lateral ventricle (Fig. 1C). Hence, emergency ventriculostomy on the left side was performed. After this second procedure, the pupils became isochoric again but were still middilated and nonreactive to light.

FIG. 1
FIG. 1

A: Preoperative axial CT scan showing a central, acute, hemorrhagic lesion and hydrocephalus. B: Preoperative coronal CT scan showing an acute hemorrhage in the right thalamus and obstruction of the foramen of Monro causing acute hydrocephalus. C: Axial CT scan obtained after placement of a right frontal EVD. The left lateral ventricle is entrapped. D: Axial CT scan showing resolution of the hydrocephalus after a left frontal EVD was placed.

The patient was transferred to the intensive care unit, and his condition slightly improved to a GCS score of 5 with abnormal flexion of the upper extremities. A repeat CT scan showed resolution of the hydrocephalus and a stable intracerebral hemorrhage (Fig. 1D). For further evaluation, magnetic resonance imaging (MRI) was conducted, revealing a hemorrhagic ring-enhancing lesion in the right thalamus, corroborating the previous suspicion of tumor-related hemorrhage (Fig. 2A, B, and D). Extensive diffusion restrictions of the midbrain and brainstem were seen because of the central herniation that had occurred (Fig. 2C).

FIG. 2
FIG. 2

A: Axial susceptibility weighted sequence showing the hemorrhagic lesion in the right thalamus. B: Axial T1-weighted image with contrast showing ring enhancement of the lesion. C: Axial diffusion weighted image showing infarction in the midbrain. D: Three-dimensional reconstruction of the relevant anatomical structures (lateral view). Brown indicates the lesion in the right thalamus; blue, the ventricles; beige, the brainstem; and yellow, the remaining intact thalamus.

After 9 days without clinical improvement, the absence of brainstem reflexes, and the described extensive brain infarctions on MRI, it was decided together with the patient’s family to discontinue medical treatment. The patient was extubated, and he died shortly afterward.

Brain autopsy revealed a DMG of the right thalamus with H3 K27 alteration (WHO grade 4) (Fig. 3). Histomorphology showed a pleomorphic glial tumor with necrosis and extensive vascular proliferation, whereas the methylation profile was consistent with a DMG, H3 K27 altered (H3 K27–mutant or EZHIP-overexpressed subtype).4 Accordingly, immunohistochemistry showed diffuse nuclear positivity with mutation-specific antibodies against histone H3 K27M. Central herniation due to acute obstructive hydrocephalus was considered the cause of death.

FIG. 3
FIG. 3

A: Macroscopic coronal brain cut showing the hemorrhagic lesion in the right thalamus with perifocal hemorrhagic infarction. B and C: Hematoxylin and eosin staining of the tumor reveals a pleomorphic tumor mass with necrosis and vascular endothelial proliferation. Orange arrow indicates necrosis; green arrows, vascular endothelial proliferation. D: Immunohistochemistry using antibodies against mutant H3 K27M shows nuclear staining in tumor cells but not endothelial cells. Bar = 500 µm (B) and 100 µm (C and D).

Literature Review

A systematic literature review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.5 The PubMed and Embase databases were searched for relevant publications up to the end of August 2023. For the database search, a combination of the terms “diffuse midline glioma,” “H3 K27,” “case report,” and “case series” was used. Full-text publications in the English language reporting adult cases of H3 K27–mutant or –altered DMG were included if information about at least 3 of the following items was provided: patient characteristics, lesion location, treatment, histological/molecular analysis, and survival data. Pediatric and spinal cases of DMG were excluded. Publications were included in the review if they were appraised as having sufficient quality according to the National Institutes of Health Quality Assessment Tool For Case Series Studies and the Joanna Briggs Institute Critical Appraisal Checklist for Case Reports (Supplemental Tables 13). Outcomes are provided as a percentage of cases with available data.

Of 89 identified publications, 19 met the inclusion criteria (Supplemental Table 1).3,6–23 The study identification and selection process are outlined in the PRISMA flowchart (Supplemental Fig. 1).5 Ten (53%) of the included publications were retrospective case series, and the remaining 9 (47%) were case reports. The included publications comprised a cumulative cohort of 244 adult patients. Median age was 33 years (range 18–73 years), and there were slightly more male patients (n = 129, 55%). The most common tumor location was the thalamus (n = 110, 54%; n = 1, bilateral involvement), followed by the brainstem (n = 52, 25%). In the remaining patients (n = 42, 21%), tumors were located in the basal ganglia, ventricles, cerebellum, pineal region, and suprasellar space. Presenting symptoms were described in 44 cases (18%). The most common symptoms at presentation were cranial nerve dysfunction (n = 21, 48%), motor deficits (n = 19, 43%), headache (n = 6, 14%), and sensory deficits (n = 4, 9%). Headache was related to hydrocephalus in 4 (9%) cases. Although some radiological signs of intratumoral hemorrhage were described in 6 (2%) cases, there was only 1 patient (0.4%) who had a large tumor-related hemorrhage leading to a fulminant clinical course. This patient was a 26-year-old female with a known H3 K27–altered DMG, who had delivered a healthy child by cesarean section (without any hypertensive episodes). On postpartum day 2, the patient was found comatose due to a large tumor-related hemorrhage and died a few days later.23 Of the 72 (30%) cases reporting treatment modalities, 35 (49%) had a subtotal or partial tumor resection, 29 (40%) underwent biopsy, and 7 (10%) had gross-total resection. In one case (1%), the diagnosis was made on the basis of cytology obtained with a lumbar puncture. Regarding adjuvant therapies, 62 (90%) patients received radio- and chemotherapy (mainly temozolomide), 4 (6%) had only radiotherapy, and 3 (4%) declined any form of treatment. When an extended molecular analysis was performed (n = 166, 68%), P53 and ATRX alterations were found to be the most common genetic mutations (n = 87 [52%], n = 55 [33%], respectively), in addition to the H3 K27 alteration. Median overall survival was 16 months, with a range from 2 to 23 months.

Patient Informed Consent

The necessary patient informed consent was obtained in this study.

Discussion

Observations

As described in this review, adult H3 K27–altered DMGs presenting with a large tumor-related hemorrhage leading to acute hydrocephalus and a fulminant clinical course are rare. The presented case has important implications for the evaluation of young adult patients presenting with brain hemorrhages located in the midline.

H3 K27–altered DMGs are described mainly in children, with the brainstem reported as the most common tumor location (63%).3 Pediatric pontine DMGs are also known as diffuse intrinsic pontine gliomas and represent up to 80% of all pediatric brainstem tumors.24 The thalamus is the second most common tumor location of pediatric DMGs (19%),3 with bilateral thalamic involvement reported in 15% of those cases.24

In the adult population, the thalamus was the most common tumor location (54%), with only one case of bilateral thalamic involvement.19 The second most common location in adults was the brainstem (25%). Although the imaging characteristics of H3 K27–altered DMGs are highly variable in terms of contrast enhancement, necrosis, and edema, intratumoral hemorrhagic signs are rarely reported in adult cranial cases.25,26 However, pediatric and spinal H3 K27–mutant DMGs seem to exhibit more intratumoral hemorrhages.27–29 In rare cases, H3 K27–altered DMGs are associated with gliomatosis cerebri growth pattern,20 multifocal manifestations,14,15,19 and metastases located outside the central nervous system.13

Regarding the surgical management of adult H3 K27–altered DMGs, subtotal/partial tumor resection and biopsy were the most common procedures, which is not surprising, given the highly eloquent location of these tumors. Concerning surgical management in the presented illustrative case, an alternative strategy could have involved an endoscope to perform a septostomy to overcome the bilateral obstruction of the foramen of Monro rather than placing bilateral EVDs. If an endoscope had been used, a biopsy of the lesion could have been performed during the same procedure. With a biopsy, the diagnosis could have been made earlier, which would have helped the team provide appropriate counsel to the patient’s family and in the decision-making process.

The prevalence of the H3 K27 mutation in adult midline glioma ranges from 13% to 53%.9,11,30,31 According to the literature review, P53 and ATRX alterations were found to be the most common genetic mutations associated with the H3 K27 alteration in adult DMGs. Conversely, recent studies have found that IDH1/IDH2 mutations and MGMT promoter methylation were frequently absent in this tumor, which contributes to its poor response to temozolomide and its dismal prognosis.17,32 Moreover, survival depends on the extent of resection and the applied radiation doses, which are both limited, given the typical locations of DMGs. Even if life expectancy is very limited in H3 K27–altered DMGs, adults appear to have a slightly better prognosis than children, which makes the presented case notable.3 Although the H3 K27 mutation has been shown to be a poor prognostic factor in children and younger adults, its presence in older adults does not seem to be associated with a worse prognosis than H3 K27 wild-type high-grade midline gliomas.10,11,33

Limitations

The main limitation of this report lies in its nature. This case report does not aim to generate evidence for a possible association between H3 K27–altered DMGs and other factors, such as the potential for tumor-related hemorrhage. Rather, it aims to increase the awareness of a rare and particular clinical manifestation of adult DMGs. Additionally, the significance of the systematic review remains limited because of the scarce literature. Its conclusions rely primarily on the quality of the included publications.

Lessons

Although typically described in the pediatric population and located in the pons, H3 K27–altered DMG should also be considered in young adult patients with a tumor located in the midline, particularly if the lesion is located in the thalamus or brainstem. In rare cases, H3 K27–altered DMGs can present with an acute tumor-related hemorrhage, leading to acute obstructive hydrocephalus and a fulminant clinical course.

Acknowledgments

We thank Ursula and André Schoepfer for their support in sharing this case report with the medical community. We also thank Jürgen Hench and Stephan Frank for the histopathological and molecular diagnostics. We thank Thomas Johnstone for proofreading the article.

Author Contributions

Conception and design: Rychen, Poletti, Soleman, Mariani. Acquisition of data: Poletti, Marques, Deigendesch, Mariani. Analysis and interpretation of data: Poletti, Marques, Deigendesch, Guzman. Drafting the article: Rychen, Poletti, Marques. Critically revising the article: Rychen, Marques, Deigendesch, Soleman, Guzman. Reviewed submitted version of manuscript: Rychen, Poletti, Soleman, Mariani, Guzman. Approved the final version of the manuscript on behalf of all authors: Rychen. Administrative/technical/material support: Guzman. Study supervision: Soleman, Mariani.

Supplemental Information

Online-Only Content

Supplemental material is available with the online version of the article.

Supplemental Tables and Figure. https://thejns.org/doi/suppl/10.3171/CASE23598.

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Supplementary Materials

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  • FIG. 1

    A: Preoperative axial CT scan showing a central, acute, hemorrhagic lesion and hydrocephalus. B: Preoperative coronal CT scan showing an acute hemorrhage in the right thalamus and obstruction of the foramen of Monro causing acute hydrocephalus. C: Axial CT scan obtained after placement of a right frontal EVD. The left lateral ventricle is entrapped. D: Axial CT scan showing resolution of the hydrocephalus after a left frontal EVD was placed.

  • FIG. 2

    A: Axial susceptibility weighted sequence showing the hemorrhagic lesion in the right thalamus. B: Axial T1-weighted image with contrast showing ring enhancement of the lesion. C: Axial diffusion weighted image showing infarction in the midbrain. D: Three-dimensional reconstruction of the relevant anatomical structures (lateral view). Brown indicates the lesion in the right thalamus; blue, the ventricles; beige, the brainstem; and yellow, the remaining intact thalamus.

  • FIG. 3

    A: Macroscopic coronal brain cut showing the hemorrhagic lesion in the right thalamus with perifocal hemorrhagic infarction. B and C: Hematoxylin and eosin staining of the tumor reveals a pleomorphic tumor mass with necrosis and vascular endothelial proliferation. Orange arrow indicates necrosis; green arrows, vascular endothelial proliferation. D: Immunohistochemistry using antibodies against mutant H3 K27M shows nuclear staining in tumor cells but not endothelial cells. Bar = 500 µm (B) and 100 µm (C and D).

  • 1

    Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016;131(6):803820.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Louis DN, Perry A, Wesseling P, et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. 2021;23(8):12311251.

  • 3

    Zheng L, Gong J, Yu T, et al. Diffuse midline gliomas with histone H3 K27M mutation in adults and children: a retrospective series of 164 cases. Am J Surg Pathol. 2022;46(6):863871.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Capper D, Jones DTW, Sill M, et al. DNA methylation-based classification of central nervous system tumours. Nature. 2018;555(7697):469474.

  • 5

    Moher D, Liberati A, Tetzlaff J, Altman DG Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Bhattarai AM, Mainali G, Jha P, et al. Diffuse midline glioma H3K27M mutation in adult: a case report. Ann Med Surg (Lond). 2022;76:103567.

  • 7

    Chen X, Zhong L, Lin J, Yu J A rare case of adult diffuse midline glioma with H3 K27M mutant in the prepontine cistern. J Int Med Res. 2021;49(1):300060520981266.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Dono A, Takayasu T, Ballester LY, Esquenazi Y Adult diffuse midline gliomas: clinical, radiological, and genetic characteristics. J Clin Neurosci. 2020;82(Pt A):18.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Ebrahimi A, Skardelly M, Schuhmann MU, et al. High frequency of H3 K27M mutations in adult midline gliomas. J Cancer Res Clin Oncol. 2019;145(4):839850.

  • 10

    Enomoto T, Aoki M, Hamasaki M, et al. Midline glioma in adults: clinicopathological, genetic, and epigenetic analysis. Neurol Med Chir (Tokyo). 2020;60(3):136146.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Hu XM, Nie XY, Xu KL, et al. H3K27M mutation doesn’t mean worse prognosis in old patients. Front Oncol. 2022;12:912166.

  • 12

    Jang SW, Song SW, Kim YH, et al. Clinical features and prognosis of diffuse midline glioma: a series of 24 cases. Brain Tumor Res Treat. 2022;10(4):255264.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Li S, Lai M, Zhen J, et al. Bone metastases in an adult patient with diffuse midline glioma: a case report. Neurooncol Adv. 2021;3(1):vdaa156.

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