A 4-year-old female presented with medically refractory seizure for 14 months. The preoperative magnetic resonance imaging (MRI) showed the mass in the temporal with slight hypointense on T1-wighted image (T1WI) (Fig. 1. A), hyperintense on T2-weighted image (T2WI) (Fig. 1. B) and on Flair sequence (Fig. 1. C). After the enhancement, the lesion was mildly enhanced (Fig. 1. D). The CT scan showed that there was obvious calcification within tumor (Fig. 1. E). The patient underwent a gross total mass resection in the right anterior and medial temporal that confirmed by postoperative CT (Fig. 1. F). Postoperatively, the patient was only treated with antiepileptic therapy and followed by observation. After nine months, tumor recurrence was found by MRI. Followed by second operation, the patient was treated with chemotherapy (oral temozolomide and antiepileptic drugs) and local radiotherapy. At 58-month follow-up after the second operation, no epileptic seizures and tumor recurrence were found. This study was approved by the ethical committee of Beijing Sanbo Brain Hospital.
Histologically, the lesion located in the cortex involving with the hippocampus and subarachnoid space. The tumor contained two different components (Fig. 2). The major component presented the GG’s features of glial and neuronal cell elements combination. The glial cells with mild nuclear atypia resembled fibrillary astrocytoma. Occasional mitoses were observed in the glial component. The neuronal cells appeared the features of dysplastic ganglion cells, which included the vacuolar nucleus and obvious nucleoli. There were dystrophic calcification and prominent capillary network. The neoplastic glial cells had diffused immunoreactivity for GFAP, S-100, Nestin, OLIG2. Neuronal proteins markers, such as MAP2, synaptophysin (Syn), chromogranin-A (CgA), neurofilaments (NF) and NeuN, displayed scattered positivity in the dysplastic neurons. CD34 staining was negative in this case. BRAFV600E was positive in both glial and neuronal cells. The Ki-67 staining showed positivity only in the glial component as a ratio about 1–2%. The minor component (< 5%) was a heterogeneous high-grade glioma characterized astroblastic-like pseudorosettes clusters, distributing among the major component. Astroblastic-like pseudorosettes were composed of elongated tumor cells containing abundant esosinophilic cytoplasm. Tumor cells distributed around the blood vessels in single-layered or pseudostratified form with a broad process. Mitoses were about 4–6 per 10 high-power fields. Astroblastic-like pseudorosettes presented diffused immunoreactivity for S-100, Nestin, Vimentin, and BRAFV600E, but were negative for GFAP, OLIG2, Syn, NF, NeuN, and CD34. EMA immunoreactivity showed a patchy pattern as dot-like perinuclear structures. The Ki-67 proliferation index was up to 15%. Microvascular proliferation and necrosis were not observed. The heterogeneous high-grade glioma characterized astroblastic-like pseudorosettes became the major component at tumor recurrence (Fig. 3). However, the minor component (about 20%) with mild nuclear atypia was similar to low-grade fibrillary astrocytoma, there was not obvious dysplastic neurons or ganglion cells. For both components in the recurrence tumor sample, immunohistochemical characteristics were also similar to the initial.
Targeted DNA sequencing was performed in formalin-fixed paraffin-embedded samples (425-cancer-relevant genes, Geneseeq Technology Inc.) (Supplementary Table 1). BRAF mutation (c.1799T > A, p.V600E) was identified with the mutant allele at a frequency of 30.84% (Fig. 4. A). The deletion copy number variations (CNV) of CDKN2A (copy number: 0.2984), CDKN2B (copy number: 0.3259), PTEN (copy number: 0.5346), and BMPR1A (copy number: 0.5229) were also be detected in this case (Fig. 4. B). Meanwhile, fluorescence in situ hybridization (FISH) was performed with MN1 break-apart probe and MYB–QKI fusions probe in the astroblastoma-like pseudorosettes. The results of FISH were all negative that different from astroblastoma and angiocentric gliomas.
The final pathological diagnosis was primary AGG consisted of low-grade/begnin GG and a heterogeneous high-grade glioma characterized astroblastic-like pseudorosettes. BRAFV600E mutation, CDKN2A homozygous deletion, and deletion of PTEN and BMPR1A were observed. Although CD34 is negative which is consistently expressed in GGs (86.7%), we still diagnosed the major component as low-grade GG since it fulfilled other GG criteria established by : 1) children with medically refractory seizure and tumor located in the temporal; 2) morphological features consisted of neoplastic glial cells and dysplastic ganglion cells; 3) positive staining of BRAFV600E in both glial and dysplastic ganglion cells. About the heterogeneous high-grade glioma characterized astroblastic-like pseudorosettes, it was diagnosed as anaplastic glial component of AGG.