MEDICINE

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

Julia Velz1,2 & Marian Christoph Neidert1,2 & Kirsten Struckmann2,3& Marc Hackius2,4 & Menno Germans1,2 &

Oliver Bozinov1,2 & Elisabeth Rushing2,5

Accepted: 21 September 2018 /Published online: 18 October 2018# Springer Nature Switzerland AG 2018 2018

AbbreviationsCSF Cerebrospinal fluid examinationGFAP Glial fibrillary acidic proteinMRI Magnetic resonance imaging

Introduction

Spinal cord tumors account for 2–4% of central nervous sys-tem neoplasms in adults, the majority comprising low-gradegliomas of ependymal or astrocytic origin [7]. Only 10% areastrocytomas, which are almost exclusively located in theintramedullary compartment. Malignant astrocytomas of thespinal cord, found mostly in young adults in the second andthird decade, are rare and the prognosis is dismal [8, 14]. Onmagnetic resonance imaging (MRI), such tumors appear in thecervical or thoracic cord as expansive, intramedullary masseswith heterogeneous contrast enhancement [8, 14, 17].Exceedingly rare is leptomeningeal gliomatosis, characterizedby extensive dissemination of neoplastic glial cells in theleptomeninges. Most high-grade cases arise in the setting ofintracranial glioblastoma, which has been reported to seedalong 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 landscapeof high-grade spinal astrocytomas [1, 3, 11, 16]. The mostcommon finding is the H3 K27M mutation, which corre-sponds to the Bdiffuse midline glioma, H3 K27M mutant,^ arecently introduced entity in the revised fourth edition of theWHO 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 thatharbor the H3 K27M mutation are associated with a 2-yearsurvival rate of < 10% and therefore correspond to WHOgrade IV [7]. This entity arises in midline locations, includingthe thalamus, pons, and spinal cord and typically affects chil-dren and young adults [7].

Here, we report the case of a 25-year-old female, whopresented with rapidly progressive meningeal symptomsand a rapidly fatal course due to leptomeningealg l iomatos is , H3 K27M mutant . Al though rare ,leptomeningeal gliomatosis should be considered in thedifferential diagnosis of patients with rapidly progressivemeningea l symptoms and imaging evidence ofleptomeningeal enhancement. Early operative explorationand pathological evaluation are essential to provide thecorrect diagnosis.

Case Report

A 25-year-old woman presented to an external hospital withincreasing headache and emesis, which developed over thecourse of a few days. Neurological examination revealed onlymild nuchal rigidity, with no evidence of focal neurologicaldeficits. The patient reported a respiratory infection 5 weeksearlier. MRI showed basal leptomeningeal enhancement espe-cially in the area of the medulla oblongata and the cervicalspinal cord (Fig. 1). Cerebrospinal fluid examination (CSF)showed a slight increase in cells and lactate with a massiveprotein elevation (37 cells/μl, lactate 3.0 mmol/l; total protein39.8 g/l). In view of the clinical findings and the recent history

This article is part of the Topical Collection on Medicine

* Julia Velzjulia.velz@usz.ch

1 Department of Neurosurgery, Clinical Neuroscience Center,University Hospital Zurich, Frauenklinikstr. 10,8091 Zurich, Switzerland

2 University of Zurich, Zurich, Switzerland3 Department of Pathology and Molecular Pathology, University

Hospital Zurich, Zurich, Switzerland4 Department of Neurology, Clinical Neuroscience Center, University

Hospital Zurich, Zurich, Switzerland5 Department of Neuropathology, Clinical Neuroscience Center,

University Hospital Zurich, Zurich, Switzerland

SN Comprehensive Clinical Medicine (2019) 1:15–19https://doi.org/10.1007/s42399-018-0007-6

of an antecedent respiratory infection, basal meningitis wasthe working diagnosis. Inflammatory diseases such asneurosarcoidosis and rheumatoid arthritis as well asleptomeningeal gliomatosis, although initially deemed unlike-ly, were considered in the differential diagnosis. The patientwas started on acyclovir, ceftriaxone, and anti-tuberculousmedication as well as steroids. Despite therapy, the patientreported progressive numbness over her trunk and both lowerextremities. Neurological examination confirmed sensorimo-tor deficits in the lower extremities. MRI of the thoracic spinerevealed a new nodular contrast-enhancing, intramedullarymass in the thoracic spine with cord compression (Fig. 2).The patient was immediately referred to our hospital with asuspected 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 attenuatedanal sphincter tone. MRI of the entire neuraxis revealed ex-tensive leptomeningeal and partially nodular contrast en-hancement throughout the dural sac, basal cisterns, and pitu-itary stalk consistent with leptomeningeal carcinomatosis,lymphoma, or possibly leptomeningeal seeding of a pilocyticastrocytoma. Nevertheless, a granulomatous infectious/inflammatory process (tuberculosis, neurosarcoidosis) couldnot be excluded. In view of the clinical course, CSF examina-tion, and MRI findings, infectious meningitis was deemedincreasingly unlikely. Accordingly, over the next days, antivi-ral and bacterial therapy was stopped. Extensive CSF as wellas blood testing was negative for human immunodeficiencyvirus (HIV), Borrelia, Brucella, Treponema, Mycoplasma,Mycobacteria, cytomegalovirus (CMV IgG and IGM),Epstein-Barr virus (EBV IgG and IGM), HSV1/2,

Fig. 2 H3 K27M-mutant spinal glioblastoma with leptomeningealgliomatosis. Sagittal contrast-enhanced T1-weighted MRI of the cervical(a), thoracic (b), and lumbar compartment (C) shows extensive

leptomeningeal, partially diffuse, and partially nodular contrastenhancement throughout the dural sac, basal cisterns, and pituitary stalkconsistent with leptomeningeal gliomatosis

Fig. 1 Axial (a) and sagittal (b)contrast-enhanced T1-weightedMRI displays basalleptomeningeal enhancementalong the medulla oblongata andcervical spinal cord

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tuberculosis (TBC) antigen test, and anti-NMO-Ab. Anhemilaminectomy and intramedullary biopsy at the level ofTh2/Th3 was performed and frozen section confirmed thesuspicion of a high-grade malignant tumor. The next day, thepatient experienced acute neurological deterioration with pro-gressive paraparesis and was started on lomustine 160 mg. Inaddition, the patient underwent palliative emergency irradia-tion with 11 × 2.5 to 27.5 Gy for 14 days. Histopathologicalexamination revealed a glioblastoma, WHO grade IV H3K27M mutant on immunostaining. Initially, the patient expe-rienced improvement of her neurological deficits under theabovement ioned chemotherapy and i r rad ia t ion .Nevertheless, on day 12 of irradiation, the patient experiencedan acute decline of her neurological status with loss of con-sciousness. MRI of the neuraxis revealed massive progressionof the leptomeningeal tumor seeding, especially in the poste-rior fossa (Fig. 3). One week later, CT scan revealed hydro-cephalus with beginning tonsillar herniation and the patientdied 6 weeks after initial presentation.

Histopathology

Microscopic examination of the biopsy revealed a mitoticallyactive neoplasm composed of closely apposed neoplastic cells(HE, Fig. 4a) that immunolabeled with glial acidic fibrillaryprotein (GFAP, Fig. 4b). Microvascular proliferation was not-ed, thus fulfilling the diagnostic criteria of glioblastoma.Immunohistochemical preparations with the IDH1 R132H an-tibody were negative and nuclear staining was preserved with

ATRX antibody (not shown). Of note, H3 K27M immunohis-tochemistry revealed nuclear positivity of the tumor cells (Fig.4d). Accordingly, an integrated diagnosis of glioblastoma, H3K27M mutant, WHO grade IV was rendered.

Discussion

To our knowledge, this is the first case of primaryleptomeningeal H3 K27M-mutant spinal glioblastoma.Although meningitis is the most common cause of meningealsymptoms in young adults, neoplasms should be considered inthe differential diagnosis. Due to unspecific presenting symp-toms, diagnosis is often delayed when CSF studies are nega-tive. Prompt pathological evaluation is crucial for establishingthe diagnosis and directing management.

Molecular characterization of glial neoplasms has revolu-tionized our understanding of the oncogenic pathways leadingto gliomagenesis [1, 4, 12, 15, 18]. Conventional histopatho-logic criteria are now routinely complemented by molecularanalyses in order to guide therapy and predict outcome [12,18]. Nevertheless, only isolated case reports and small seriesaddress the molecular profile of spinal cord astrocytomas [3,11, 16]. The most common alteration is the K27Mmutation inthe H3F3A or HIST1H3B/HIST1H3C genes, which encodethe histone H3 variants H3.3 and H3.1. and occur predomi-nantly in children and young adults (median age 10.5 years,range 5–23 years) in midline locations, including the thala-mus, pons, and spinal cord [9]. K27Mmutations inH3F3A orHIST1H3B/HIST1H3C have been identified as early hallmarkevents driving gliomagenesis [18]. Somatic mutations in theH3F3A gene, leading to key regulatory post-translationalmodifications, have been identified in one third of pediatricglioblastoma [15]. These mutations are mutually exclusive

Fig. 4 a HE-stain showing adensely cellular glial neoplasm. bThe tumor cells immunolabeledwith GFAP, whereas foci ofmicrovascular proliferation arenegative. c The MIB1-proliferation index focally reaches50%. d Nuclear staining of thetumor cells corresponds toimmunohistochemical evidenceof the histone H3 K27Mmutation

�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) MRIreveals massive leptomeningeal tumor spread

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with IDH1 and IDH2 mutations in keeping with the low rateof IDH mutations identified in spinal gliomas [18, 19].

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

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

Compliance with Ethical Standards

Conflict of Interest The authors declare that they have no conflict ofinterest.

Informed Consent Informed consent was provided from the patient’sparents.

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