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The 2016 WHO Classification of tumours of the central nervous system has introduced a new histomolecular entity, the midline diffuse glioma, H3K27M-mutant [8]. This entity represents an infiltrative high-grade glioma (HGG) (grade IV) of the pons and the brainstem, which mainly effects children. It harbors K27M mutations of H3F3A, HIST1H3B/C or HIST2H3A/C genes. In the pons, morphological differential diagnoses are numerous with a large spectrum of tumours ranging from benign such as pilocytic astrocytoma to malignant such as embryonal tumour with multilayered rosettes (ETMR). From the reclassification of CNS-PNETs in the study by Sturm et al., HGG-MYCN was described in 28/323 cases (9%), mainly located in the cerebral hemispheres. Moreover, in a recent series of pontine gliomas, three molecular subgroups were defined: H3K27M-mutant, MYCN-amplified and silent [1]. The MYCN subgroup was the least frequent, with only 8% of cases (4/47) [1]. This corresponds to a very rare tumour and very few radiological, clinical and histopathological data are available in the literature. In our center, six cases of HGG-MYCN were diagnosed by whole exome sequencing (WES) based on the co-amplification of MYCN and ID2 (2 cases from BIOMEDE cohort) [3]. Herein, our aim is to describe the clinical, imaging, histopathological, immunohistochemical and molecular features of these cases to better characterize them. Concordant with recent literature, the median age of our patients was 3.7 (1 to 7 years old) and concerned 4 girls (Cases 2, 3, 4 and 6) and 2 boys (Cases 1 and 5) [1]. Clinically, all our patients presented similarly to midline diffuse gliomas, H3K27M-mutant, with a short clinical history (< 6 months of symptom duration) and the presence of a pontine tumour infiltrating at least 50% of the pons. Radiologically, all tumors were centered in the pons, with variable involvement of the mesencephalon and the middle cerebellar peduncle. None was calcified nor hemorrhagic. HGG-MYCN displayed necrosis at first presentation, with annular enhancement, larger than in H3K27M gliomas. Furthermore, diffusion was more restricted than classically reported in diffuse intrinsic pontine gliomas (n = 5, median Apparent Diffusion Coefficient: 570 μm/s, IQR [543–734], versus 1504 μm/s in Calmon et al.), and relative Cerebral Blood Flow was higher using arterial spin labeling (n = 4, median 2.1, IQR [1.7–2.8] versus 1.1 in Calmon et al.) Relative Cerebral Blood Volume using dynamic susceptibility contrast perfusion MRI was in the usual range (n = 3, values: 1.1, 1.8, 3.8) (Fig. 1) [2]. All patients died of their disease, two directly following a surgical biopsy, one (Case 3) after 1 month of chemotherapy (VP16 carboplatin) and three (Cases 4, 5 and 6) after radiotherapy and chemotherapy. The mean overall survival of our patients was 3.8 months and the median overall survival was 4.2 months, which is shorter than midline diffuse glioma, H3 K27M-mutant [5, 6, 10]. Histopathologic examination showed a well circumscribed tumor from the parenchyma with only a few cells infiltrating the surrounding parenchyma (Fig. 2a). The multinodular, undifferentiated neoplasm presented with a subtle transition between spindle cells and nodules of epithelioid cells (Fig. 2a-e). In all cases, malignancy was obvious with high mitotic count, high proliferation index (mean MIB index of 51%), necrosis and microvascular proliferation (Fig. 2 c and f). The neoplastic cells had round to oval nuclei, vesicular to coarse chromatin, prominent nucleoli and a scant to moderate

An integrative radiological, histopathological and molecular analysis of pediatric pontine histone-wildtype glioma with MYCN amplification (HGG-MYCN)