Case Report: Five Adult Cases of H3K27-Altered Diffuse Midline Glioma in the Spinal Cord

Abstract

BackgroundDiffuse midline glioma with H3K27-altered (DMG-H3K27a) is a novel tumor entity of the pediatric-type diffuse high-grade tumor in the latest WHO CNS 5. It mostly affects children and is only rarely found in adults. The tumor has a high level of aggressiveness, with a rapid progression and bad prognosis. In adults, the spinal cord is the most common site of DMG-H3K27a. Rare adult cases of primary DMG-H3K27a in the spinal cord were reported in this study, together with clinico-histopathologico-radiographic data.MethodsFrom January 2016 to December 2020, we conducted a retrospective study of five adults with primary DMG-H3K27a in the spinal cord, analyzing their clinical, pathohistological, and radiographic datasets from the first diagnosis to follow-up.ResultsAll five patients were diagnosed for the first time and were given full treatment. In three of the five patients, post-operative follow-up revealed tumor recurrence. The longest survival of the five patients was 45 months at the time of report submission, while the longest progression-free survival (PFS) following surgery was 20 months. Immunohistochemical studies showed the tumors featured aggressive behavior (grade 4) and were positive for the H3K27M mutation. The radiographic appearances were varied, but they were all initially mistaken as benign. DMG-H3K27a in the spinal cord was characterized by isointense/hyperintense on T1WI and isointense/hyperintense on T2WI, as well as cystic necrosis and peripheral spinal cord edema, as well as central canal enlargement and other types of enhancement.ConclusionThis is the first case report focusing on adult DMG-H3K27a of the pediatric-type diffuses high-grade gliomas in the spinal cord. In our cases, we discovered the following: 1) adults had a better prognosis with a longer PFS compared with prior pediatric reports; 2) despite aggressive behavior under the microscope, radiographic appearances of the tumors were less aggressive; and 3) adjuvant treatment, including TCM, may have played a role in the prognosis.

A rare case of H3K27-altered diffuse midline glioma with multiple osseous and spinal metastases at the time of diagnosis

“…Interestingly, a decrease in H3K27M plasma circulating tumor deoxyribonucleic acid can be a predictor of tumor response to radiotherapy, which was in agreement with 83% of the analyzed patients [ 20 ]. Other studies suggest that patients with suspected gliomas at midline structures on MR should first undergo immunohistochemistry testing for H3K27M mutations, especially if tissues were difficult to collect and malignancy is difficult to diagnose based on histological examination alone [ 16 , 21 ].…”

“…It had been characterized as a diffuse midline glioma with H3K27M mutations in the 2016 WHO classification [ 1 ]. Its nomenclature has recently been changed in recognition of other altered mechanisms (e.g., EZHIP protein overexpression) which could underlie the pathogenesis of tumors [ 16 ]. Clinically, the diagnostic criteria for H3K27-altered diffuse midline glioma consist of a diffuse growing pattern (i.e., infiltrating), a midline location (including the thalamus, cerebellum, brain stem, and spinal cord), and H3K27-specific neuroglial mutations in addition to supporting histopathological and molecular evidence [ 15 – 17 ].…”

Surgical approaches to intramedullary spinal cord astrocytomas in the age of genomics

“…H3 K27M-altered diffuse midline gliomas are aggressive lesions most commonly appearing in children and young adults ( Figure 2 ) ( 87 , 92 ). Although they can appear in several midline structures, the spinal cord is the most common site of H3 K27M-altered gliomas in adults ( 93 ). They are designated WHO Grade 4, although their underlying microscopic appearance may appear Grade 2, 3, or 4 ( 88 , 94 ).…”

“…Gu et al. reported five cases of intramedullary diffuse midline gliomas with the H3K27M-alteration and noted that all were initially mistaken as benign based on their radiographic appearance ( 93 ). Interestingly, the H3K27M-alteration has not been shown to present alongside IDH mutations, suggesting the two are mutually exclusive ( 96 , 97 ).…”

“…Several studies have shown that they do not significantly worsen survival in histologic Grade 3 or 4 lesions compared to high-grade wild-type astrocytomas, illustrating that histological grade is still an important consideration in evaluating these lesions, although statistical significance in those studies may have been limited by small sample sizes ( 88 , 95 ). Adults with the H3K27M-altered gliomas may have improved prognosis compared to pediatric patients ( 93 ). Inhibition of the histone demethylase JMJD3 can increase H3K27 methylation and has shown encouraging results in in vitro and in vivo mice models of brainstem glioma, illustrating the importance of genetic analysis of astrocytomas to identify potential targeted therapeutics and improve patient outcomes ( 98 ).…”