Characteristics of gliomas in patients with somatic IDH mosaicism

Abstract

IDH mutations are found in the majority of adult, diffuse, low-grade and anaplastic gliomas and are also frequently found in cartilaginous tumors. Ollier disease and Maffucci syndrome are two enchondromatosis syndromes characterized by the development of multiple benign cartilaginous tumors due to post-zygotic acquisition of IDH mutations. In addition to skeletal tumors, enchondromatosis patients sometimes develop gliomas. The aim of the present study was to determine whether gliomas in enchondromatosis patients might also result from somatic IDH mosaicism and whether their characteristics are similar to those of sporadic IDH-mutated gliomas. For this purpose, we analyzed the characteristics of 6 newly diagnosed and 32 previously reported cases of enchondromatosis patients who developed gliomas and compared them to those of a consecutive series of 159 patients with sporadic IDH-mutated gliomas. As was the case with sporadic IDH mutated gliomas, enchondromatosis gliomas were frequently located in the frontal lobe (54 %) and consisted of diffuse low-grade (73 %) or anaplastic gliomas (21 %). However, they were diagnosed at an earlier age (25.6 years versus 44 years, p < 0.001) and were more frequently multicentric (32 % versus 1 %, p < 0.001) and more frequently located within the brainstem than sporadic IDH mutated gliomas (21 % versus 1 %, p < 0.001). Their molecular profile was characterized by IDH mutations and loss of ATRX expression. In two patients, the same IDH mutation was demonstrated in the glioma and in a cartilaginous tumor. In contrast to sporadic IDH mutated gliomas, no enchondromatosis glioma harbored a 1p/19q co-deletion (0/6 versus 59/123, p = 0.03). The characteristics of gliomas in patients with enchondromatosis suggest that these tumors, as cartilaginous tumors, result from somatic IDH mosaicism and that the timing of IDH mutation acquisition might affect the location and molecular characteristics of gliomas. Early acquisition of IDH mutations could shift gliomagenesis towards the brainstem thereby mimicking the regional preference of histone mutated gliomas.

Keywords: Glioma; IDH mutation; Maffucci; Ollier; Somatic mosaicism.

Fig. 1

MRI characteristics of the diffuse gliomas in the 6 new enchondromatosis patients and double staining with anti-IDH1R132H and anti-ATRX antibodies. Top: MRI findings of patient 1 to patient 6 at diagnosis (axial T2/fluid-attenuated inversion recovery (FLAIR) sequences) demonstrating multicentric tumors in patients 1, 2, 3 and 4. Bottom: histological characteristics of the recurrent tumor of patient 3. a Hematoxylin eosin staining demonstrating an anaplastic glioma. b IDH1 R132H expression (brown signal). c Diffuse loss of ATRX expression in tumor cells and maintained expression (brown signal) in endothelial cells. d-g) Double staining demonstrating rare cells with a normal oligodendrocyte (black arrowheads) or astrocyte (black arrows) morphology expressing both IDH1 R132H (red signal) and ATRX (brown signal) (inserts showing same cells at higher magnification) and tumor cells with abnormal morphology and expressing IDH1 R132H but not ATRX (white arrows)

Fig. 2

Age at glioma in patients with enchondromatosis and sporadic IDH mutated gliomas according to grade and 1p/19q co-deletion. Y axis: age at glioma diagnosis (years). X axis: OD/MS: enchondromatosis patients with glioma, IDH: patients with sporadic IDH mutated gliomas without 1p/19q co-deletion, Codel: patients with sporadic IDH mutated gliomas with 1p/19q co-deletion. Median age at glioma diagnosis, was lower in OD/MS than in IDH patients (25.6 vs 41 years, p < 0.001) and in IDH than in Codel patients (41 years vs 50.8 years, p < 0.001). The difference remained significant when taking into account only LGG (OD/MS vs IDH patients: 26.9 vs 39 years, p < 0.001; IDH vs Codel patients: 39 vs 49 years, p = 0.01)