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SN Comprehensive Clinical Medicine

, Volume 1, Issue 1, pp 15–19 | Cite as

A Rare Case of Diffuse Midline Glioma, H3 K27M Mutant, of the Spinal Cord Mimicking Meningitis

  • Julia VelzEmail author
  • Marian Christoph Neidert
  • Kirsten Struckmann
  • Marc Hackius
  • Menno Germans
  • Oliver Bozinov
  • Elisabeth Rushing
Medicine
  • 338 Downloads
Part of the following topical collections:
  1. Topical Collection on Medicine

Abbreviations

CSF

Cerebrospinal fluid examination

GFAP

Glial fibrillary acidic protein

MRI

Magnetic resonance imaging

Introduction

Spinal cord tumors account for 2–4% of central nervous system neoplasms in adults, the majority comprising low-grade gliomas of ependymal or astrocytic origin [7]. Only 10% are astrocytomas, which are almost exclusively located in the intramedullary compartment. Malignant astrocytomas of the spinal cord, found mostly in young adults in the second and third decade, are rare and the prognosis is dismal [8, 14]. On magnetic resonance imaging (MRI), such tumors appear in the cervical or thoracic cord as expansive, intramedullary masses with heterogeneous contrast enhancement [8, 14, 17]. Exceedingly rare is leptomeningeal gliomatosis, characterized by extensive dissemination of neoplastic glial cells in the leptomeninges. Most high-grade cases arise in the setting of intracranial glioblastoma, which has been reported to seed along the spine in 23% of cases [2]. There are only isolated case reports of primary leptomeningeal gliomatosis [7, 13]. Only few publications have investigated the genetic landscape of high-grade spinal astrocytomas [1, 3, 11, 16]. The most common finding is the H3 K27M mutation, which corresponds to the “diffuse midline glioma, H3 K27M mutant,” a recently introduced entity in the revised fourth edition of the WHO classification of Tumors of the Central Nervous System [6, 7]. Even when anaplastic features such as mitotic activity, vascular proliferation, and necrosis are lacking, tumors that harbor the H3 K27M mutation are associated with a 2-year survival rate of < 10% and therefore correspond to WHO grade IV [7]. This entity arises in midline locations, including the thalamus, pons, and spinal cord and typically affects children and young adults [7].

Here, we report the case of a 25-year-old female, who presented with rapidly progressive meningeal symptoms and a rapidly fatal course due to leptomeningeal gliomatosis, H3 K27M mutant. Although rare, leptomeningeal gliomatosis should be considered in the differential diagnosis of patients with rapidly progressive meningeal symptoms and imaging evidence of leptomeningeal enhancement. Early operative exploration and pathological evaluation are essential to provide the correct diagnosis.

Case Report

A 25-year-old woman presented to an external hospital with increasing headache and emesis, which developed over the course of a few days. Neurological examination revealed only mild nuchal rigidity, with no evidence of focal neurological deficits. The patient reported a respiratory infection 5 weeks earlier. MRI showed basal leptomeningeal enhancement especially in the area of the medulla oblongata and the cervical spinal cord (Fig. 1). Cerebrospinal fluid examination (CSF) showed a slight increase in cells and lactate with a massive protein elevation (37 cells/μl, lactate 3.0 mmol/l; total protein 39.8 g/l). In view of the clinical findings and the recent history of an antecedent respiratory infection, basal meningitis was the working diagnosis. Inflammatory diseases such as neurosarcoidosis and rheumatoid arthritis as well as leptomeningeal gliomatosis, although initially deemed unlikely, were considered in the differential diagnosis. The patient was started on acyclovir, ceftriaxone, and anti-tuberculous medication as well as steroids. Despite therapy, the patient reported progressive numbness over her trunk and both lower extremities. Neurological examination confirmed sensorimotor deficits in the lower extremities. MRI of the thoracic spine revealed a new nodular contrast-enhancing, intramedullary mass in the thoracic spine with cord compression (Fig. 2). The patient was immediately referred to our hospital with a suspected abscess in the region of the thoracic spinal cord, most likely due to meningitis (day 9 of initial hospitalization). At the time of admission, the patient showed nuchal rigidity, an ataxic gait, and sensory level below Th5 with attenuated anal sphincter tone. MRI of the entire neuraxis revealed extensive leptomeningeal and partially nodular contrast enhancement throughout the dural sac, basal cisterns, and pituitary stalk consistent with leptomeningeal carcinomatosis, lymphoma, or possibly leptomeningeal seeding of a pilocytic astrocytoma. Nevertheless, a granulomatous infectious/inflammatory process (tuberculosis, neurosarcoidosis) could not be excluded. In view of the clinical course, CSF examination, and MRI findings, infectious meningitis was deemed increasingly unlikely. Accordingly, over the next days, antiviral and bacterial therapy was stopped. Extensive CSF as well as blood testing was negative for human immunodeficiency virus (HIV), Borrelia, Brucella, Treponema, Mycoplasma, Mycobacteria, cytomegalovirus (CMV IgG and IGM), Epstein-Barr virus (EBV IgG and IGM), HSV1/2, tuberculosis (TBC) antigen test, and anti-NMO-Ab. An hemilaminectomy and intramedullary biopsy at the level of Th2/Th3 was performed and frozen section confirmed the suspicion of a high-grade malignant tumor. The next day, the patient experienced acute neurological deterioration with progressive paraparesis and was started on lomustine 160 mg. In addition, the patient underwent palliative emergency irradiation with 11 × 2.5 to 27.5 Gy for 14 days. Histopathological examination revealed a glioblastoma, WHO grade IV H3 K27M mutant on immunostaining. Initially, the patient experienced improvement of her neurological deficits under the abovementioned chemotherapy and irradiation. Nevertheless, on day 12 of irradiation, the patient experienced an acute decline of her neurological status with loss of consciousness. MRI of the neuraxis revealed massive progression of the leptomeningeal tumor seeding, especially in the posterior fossa (Fig. 3). One week later, CT scan revealed hydrocephalus with beginning tonsillar herniation and the patient died 6 weeks after initial presentation.
Fig. 1

Axial (a) and sagittal (b) contrast-enhanced T1-weighted MRI displays basal leptomeningeal enhancement along the medulla oblongata and cervical spinal cord

Fig. 2

H3 K27M-mutant spinal glioblastoma with leptomeningeal gliomatosis. Sagittal contrast-enhanced T1-weighted MRI of the cervical (a), thoracic (b), and lumbar compartment (C) shows extensive leptomeningeal, partially diffuse, and partially nodular contrast enhancement throughout the dural sac, basal cisterns, and pituitary stalk consistent with leptomeningeal gliomatosis

Fig. 3

Axial native (a) and contrast-enhanced (b) T1-weighted MRI. Coronal (c) and sagittal (d) contrast-enhanced T1-weighted MRI. Sagittal T1-weighted native (e, g) and contrast-enhanced (f, h) MRI reveals massive leptomeningeal tumor spread

Histopathology

Microscopic examination of the biopsy revealed a mitotically active neoplasm composed of closely apposed neoplastic cells (HE, Fig. 4a) that immunolabeled with glial acidic fibrillary protein (GFAP, Fig. 4b). Microvascular proliferation was noted, thus fulfilling the diagnostic criteria of glioblastoma. Immunohistochemical preparations with the IDH1 R132H antibody were negative and nuclear staining was preserved with ATRX antibody (not shown). Of note, H3 K27M immunohistochemistry revealed nuclear positivity of the tumor cells (Fig. 4d). Accordingly, an integrated diagnosis of glioblastoma, H3 K27M mutant, WHO grade IV was rendered.
Fig. 4

a HE-stain showing a densely cellular glial neoplasm. b The tumor cells immunolabeled with GFAP, whereas foci of microvascular proliferation are negative. c The MIB1-proliferation index focally reaches 50%. d Nuclear staining of the tumor cells corresponds to immunohistochemical evidence of the histone H3 K27M mutation

Discussion

To our knowledge, this is the first case of primary leptomeningeal H3 K27M-mutant spinal glioblastoma. Although meningitis is the most common cause of meningeal symptoms in young adults, neoplasms should be considered in the differential diagnosis. Due to unspecific presenting symptoms, diagnosis is often delayed when CSF studies are negative. Prompt pathological evaluation is crucial for establishing the diagnosis and directing management.

Molecular characterization of glial neoplasms has revolutionized our understanding of the oncogenic pathways leading to gliomagenesis [1, 4, 12, 15, 18]. Conventional histopathologic criteria are now routinely complemented by molecular analyses in order to guide therapy and predict outcome [12, 18]. Nevertheless, only isolated case reports and small series address the molecular profile of spinal cord astrocytomas [3, 11, 16]. The most common alteration is the K27M mutation in the H3F3A or HIST1H3B/HIST1H3C genes, which encode the histone H3 variants H3.3 and H3.1. and occur predominantly in children and young adults (median age 10.5 years, range 5–23 years) in midline locations, including the thalamus, pons, and spinal cord [9]. K27M mutations in H3F3A or HIST1H3B/HIST1H3C have been identified as early hallmark events driving gliomagenesis [18]. Somatic mutations in the H3F3A gene, leading to key regulatory post-translational modifications, have been identified in one third of pediatric glioblastoma [15]. These mutations are mutually exclusive with IDH1 and IDH2 mutations in keeping with the low rate of IDH mutations identified in spinal gliomas [18, 19].

Glial neoplasms rarely present as isolated leptomeningeal disease [7, 13]; H3 K27 mutation has only been described in isolated cases with primary leptomeningeal dissemination [5].

Despite recent advances, glioblastoma remains a puzzling disease with only a limited understanding of the underlying molecular alterations. Additional investigations are needed to clarify the exact frequency, clinicopathological characteristics, and genomic alterations of diffuse midline glioma, H3 K27M-mutant that may lead to the identification of innovative subgroup-specific treatments, e.g., for H3.3-mutated variants [18]. Mohammad et al. recently reported EZH2 as a potential therapeutic target for H3 K27M-mutant pediatric gliomas [10].

Notes

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Informed Consent

Informed consent was provided from the patient’s parents.

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Copyright information

© Springer Nature Switzerland AG 2018 2018

Authors and Affiliations

  1. 1.Department of Neurosurgery, Clinical Neuroscience CenterUniversity Hospital ZurichZurichSwitzerland
  2. 2.University of ZurichZurichSwitzerland
  3. 3.Department of Pathology and Molecular PathologyUniversity Hospital ZurichZurichSwitzerland
  4. 4.Department of Neurology, Clinical Neuroscience CenterUniversity Hospital ZurichZurichSwitzerland
  5. 5.Department of Neuropathology, Clinical Neuroscience CenterUniversity Hospital ZurichZurichSwitzerland

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