K27M mutation in H3F3A in ganglioglioma grade I with spontaneous malignant transformation extends the histopathological spectrum of the histone H3 oncogenic pathway

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Here we describe the presence of the mutation p.K27M of H3F3A (H3.3K27M) in two tumours of young patients with classical histopathology of ganglioglioma (grade I WHO 2007), although H3.3K27M represents a hallmark of midline High Grade Glioma (HGG).
Ganglioglioma grade I is a rare, circumscribed, glioneuronal tumour of the central nervous system (CNS) that occurs most often in young patients, most frequently in the temporal lobe and presents with seizures 1. The neuronal component consists of ganglion cells, abnormally grouped and occasionally binucleated. The glial component consists of piloid or fibrillary astrocytic elements, or of pseudo‐oligodendroglial elements. Mitoses are occasional and necrosis is absent. Eosinophilic granular bodies (EGB) and perivascular lymphocytes are associated 1. The glial component variably expresses GFAP and OLIG2 and the neuronal component variably expresses synaptophysin, chromogranin A and MAP2. The progenitor marker CD34 often shows an extravascular stellar immunostaining 1. Ki67 labelling index is usually less than 3% and p53 immunostaining is negative. The majority of gangliogliomas are benign grade I tumours, however 6% present as grade III anaplastic ganglioglioma or undergo malignant transformation. Markers to predict anaplastic transformation of grade I tumours are poorly defined 1. The most frequent genetic alterations in ganglioglioma are BRAF p.V600E mutation (40–60%), gain of chromosomes 7 (23%) and 5 (18%) 1.
Recurrent mutations in the genes H3F3A and HIST1H3B (encoding histones H3.3 and H3.1 respectively) were described in paediatric and adult HGG and carry a dismal prognosis 5. These mutations show a distinct anatomical segregation: K27M mutation of H3F3A is observed in thalamus, pons and spinal cord, K27M mutation of HIST1H3B is specifically observed in diffuse intrinsic pontine gliomas and G34R/V mutation of H3F3A is observed in the cerebral hemispheres 5. At position 27, lysine is replaced by methionine (K27M) resulting in decreased K27 trimethylation (H3K27me3) 5. H3.3K27M immunolabelling shows 100% sensitivity and specificity compared to sequencing 5. Recently, five H3.3K27M paediatric tumours with histopathology other than HGG were reported: three tumours of unclassified histopathology and harbouring BRAF V600E mutation 8, one ganglioglioma harbouring BRAF V600E mutation which underwent a delayed malignant transformation 9, a spinal pilocytic astrocytoma which underwent a delayed malignant transformation after 10 years 10. Here we extend the histopathological spectrum of H3.3K27M tumours and present two extratemporal grade I gangliogliomas with secondary malignant transformation. One paediatric midline ganglioglioma had combined H3.3K27M and BRAF V600E mutations and its long‐term malignant relapse was BRAF wild type. The second case represented a cerebellar tumour with a rapid malignant transformation.
The first case was a 12‐year‐old girl diagnosed with a partially resected right thalamic tumour. Histopathology was of a ganglioglioma grade I. The tumour was reticulin free and composed of astrocytic piloid elements, pseudo‐oligodendroglial elements and ganglionic cells associated with EGBs, lymphocytes and CD34 extravascular stellar immunostaining (Figure 1A–C). Binucleated chromogranin A positive cells and mononucleated synaptophysin expressing cells were detected (Figure 1D). The neurofilament immunolabelling confirmed the circumscribed nature of the tumour. The Ki67 labelling index was 2% (Figure 1E). The residual tumour was stable for 7 years until the patient presented with intracranial hypertension. MRI showed an in situ relapse (Figure 1G). The surgical resection was subtotal. Histopathology demonstrated an anaplastic ganglioglioma. The lesion contained low‐grade areas (Figure 1H) and anaplastic areas with high cellularity, marked atypia, mitotic activity exceeding 5 mitoses per 10 high power field (HPF), microvascular proliferation, pseudopalisading necrosis, high p53 expression and Ki67 index reaching 20% (Figure 1I). OLIG2 and GFAP were expressed by a majority of glial tumour cells. Glial and neuronal tumour cells showed loss of ATRX immunostaining (Figure 1J), H3.3K27M immunopositivity (Figure 1K) and loss of H3K27me3 immunolabelling. Mutation p.
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