A Rare Case of Diffuse Midline Glioma, H3 K27M Mutant, of the Spinal Cord Mimicking Meningitis
- 207 Downloads
Cerebrospinal fluid examination
Glial fibrillary acidic protein
Magnetic resonance imaging
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 . 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 . 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 . This entity arises in midline locations, including the thalamus, pons, and spinal cord and typically affects children and young adults .
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.
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 . K27M mutations in H3F3A or HIST1H3B/HIST1H3C have been identified as early hallmark events driving gliomagenesis . Somatic mutations in the H3F3A gene, leading to key regulatory post-translational modifications, have been identified in one third of pediatric glioblastoma . 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].
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 . Mohammad et al. recently reported EZH2 as a potential therapeutic target for H3 K27M-mutant pediatric gliomas .
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
Informed consent was provided from the patient’s parents.
- 4.Karremann M, Gielen GH, Hoffmann M, Wiese M, Colditz N, Warmuth-Metz M, Bison B, Claviez A, van Vuurden DG, von Bueren AO, Gessi M, Kühnle I, Hans VH, Benesch M, Sturm D, Kortmann R-D, Waha A, Pietsch T, Kramm CM. Diffuse high-grade gliomas with H3 K27M mutations carry a dismal prognosis independent of tumor location. Neuro-Oncology. 2018;20:123–31.Google Scholar