Bithalamic gliomas may be molecularly distinct from their unilateral high‐grade counterparts

Abstract

Bithalamic gliomas are rare cancers diagnosed based on poorly defined radiologic criteria. Infiltrative astrocytomas account for most cases. While some previous studies reported dismal outcomes for patients with bithalamic gliomas irrespective of therapy and histologic grade, others described better prognoses even without anticancer therapy. Little is known about their molecular characteristics. We reviewed clinical, radiologic, and histologic features of patients with bithalamic gliomas treated at our institution over 15 years. Targeted sequencing of mutational hotspots in H3F3A, HIST1H3B, IDH1/2, and BRAF, and genome‐wide analysis of DNA methylation and copy number abnormalities was performed in available tumors. Eleven patients with bithalamic gliomas were identified. Their median age at diagnosis was 4.8 years (range: 1–15.7). Additional involvement of the brainstem, basal ganglia, and cerebral lobes occurred in 11, 9, and 3 cases, respectively. All patients presented with hydrocephalus. Two‐thirds of the patients had a histologic diagnosis of anaplastic astrocytoma. Despite aggressive therapy, our youngest patient, the only one diagnosed before 1 year of age, is the sole long‐term survivor. DNA methylation could be performed in seven tumors, all of which clustered with the RTK I ‘PDGFRA’ subgroup by unsupervised hierarchical analysis of methylation array against a previously published cohort of 59 pediatric high‐grade gliomas. Sequencing of hotspots mutations could be done in 10 tumors, none of which harbored H3F3A p.K27 and/or the respective DNA methylation signature, and any other hotspot mutations. Amplification of MDM4 (n = 2), PDGFRA (n = 2), and ID2 combined with MYCN (n = 1) were observed in 7 tumors available for analysis. In comparison with the previously published experience with unilateral high‐grade thalamic astrocytomas where H3F3A p.K27 was present in two‐thirds of cases, the absence of this molecular subgroup in bithalamic gliomas was striking. This finding suggests that unilateral and bithalamic high‐grade gliomas may represent two distinct molecular entities.

The pediatric supratentorial MYCN-amplified high-grade gliomas methylation class presents the same radiological, histopathological and molecular features as their pontine counterparts

“…Clinical data of our cases are summarized in Table S2. The median age of pediatric HGG-MYCN (published cases and our own) was 9.0 years (range from 2 to 18) which was lower than H3 K27M (11.0 years) and H3 G34-mutant (13.0 years), RTKI (10.0 years) and RTKII subgroups (10.0 years) [1][2][3][4][5][6][7][8]10]. This difference was only significant between HGG-MYCN and H3-G34 mutant gliomas (p < 0.001) [4,5,7,8].…”

“…This difference was only significant between HGG-MYCN and H3-G34 mutant gliomas (p < 0.001) [4,5,7,8]. The sex ratio male/female for HGG-MYCN was 1.3 and 3.4, 0.6, 1.2 and 1.3 respectively for H3 G34-mutant gliomas, H3 K27M-mutant gliomas, HGG-RTKI and RTK2 (but without significant difference) [1][2][3][4][5][6][7][8]10]. HGG-MYCN were mostly located in the hemispheres (31/37 cases with available data, 83.8%), but 5 (13.5%) were thalamic and one arose from the sellar area [4,5,7].…”

“…The pediatric supratentorial MYCNamplified high-grade gliomas methylation class presents the same radiological, histopathological and molecular features as their pontine counterparts A. Tauziède-Espariat 1* , M-A Debily 2,3 , D. Castel 2,4 , J. Grill 2,4 , S. Puget 5 , A. Roux 6 , R. Saffroy 7 , M. Pagès 1,8,9,10 , A. Gareton 1 , F. Chrétien 1 , E. Lechapt 1 , V. Dangouloff-Ros 11 , N. Boddaert 11 and P. Varlet 1 Recent genomic and epigenomic analyses have pointed out the heterogeneity of tumors from a same histopathological group and have identified key oncogenic alterations that enabled the description of novel tumor entities. Thus, pediatric high-grade gliomas (HGG) comprise a heterogeneous group of tumors, including H3 K27M-mutant, H3 G34-mutant, IDH-mutant and H3/IDH-wildtype HGG.…”

“…We investigated data from five pediatric supratentorial HGG-MYCN diagnosed by DNA methylation profiling at our institution (one case included in [7]) and we pooled them with methylation class pediatric HGG-MYCN of the literature (n = 59) [4,5,7]. Therefore, we analyzed clinical, histopathological and molecular data of pediatric supratentorial HGG-MYCN and compared them to their pontine counterparts [9] and did a systematic review of four groups of supratentorial pediatric HGG (including 62 H3 K27M-mutant gliomas, 31 H3-G34 mutant gliomas, 44 HGG-RTKI and 16 HGG-RTKII) [1][2][3][4][5][6][7][8]10].…”

Pediatric Thalamic Gliomas: An Updated Review

“…Of these publications, 20 were case series (Table). 1,[4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] Histologically, the vast majority (70%-90%) of reported thalamic tumors are classified as astrocytoma. However, this literature is limited and difficult to interpret regarding histologic subtypes in children, as many studies combine age groups, are confined to more specific entities (eg, pilocytic astrocytoma (PA) or ''high-grade astrocytoma''), group biologically distinct entities (eg, PA and low-grade diffuse astrocytoma [DA] as ''low-grade astrocytoma''), or are single case reports.…”