An 8‐Year‐Old Girl with A Supratentorial Mass

Clinical History

An 8‐year‐old, previously healthy girl presented with a 3‐month history of intermittent, progressive night‐time and early morning headaches and vomiting, and a 3‐week history of left‐sided facial weakness and mild left hemiparesis. MRI showed a 5.6 × 4.3 × 4.5 cm T1 hypointense, T2/FLAIR hyperintense mass containing several scattered foci of contrast enhancement centered within the right basal ganglia and medial temporal lobe (Figure 1A). The mass demonstrated restricted diffusion, and contained no hemorrhage, necrosis, calcification or surrounding vasogenic edema. The presence of restricted diffusion and heterogenous enhancement on imaging suggested a highly cellular tumor. Given the young age of this patient, the radiological differential considerations included embryonal tumor and anaplastic ependymoma especially because of the lack of surrounding vasogenic edema. A stereotactic needle biopsy was performed. The patient was treated with conformal radiation therapy and concurrent chemotherapy with temozolomide, followed by temozolomide and lomustine according to the Children's Oncology Group ACNS0423 protocol. She had clinical and radiographic response to treatment until 7 months following diagnosis, when her hemiparesis returned and she developed vision loss. MRI revealed marked interval progression of her disease with extension into her right optic tract, optic chiasm and brainstem. She was then treated with bevacizumab and irinotecan. Two‐month later, she developed further progression with new subependymal spread and extension into the left cerebrum and brainstem. Her therapy was discontinued and she expired 12 months from the date of her initial diagnosis.

Figure 1.

 

Microscopic and Molecular Pathology

Histological examination of the biopsy material showed a high‐grade diffuse glioma. Throughout, the tumor cells showed a rather uniform appearance (Figure 1B). Other notable features included the focal presence of myxoid/mucinous background, delicate thin‐walled capillaries and pericellular clearing with absence of definite microvascular proliferation and/or necrosis. While the tumor cells displayed deceptively monomorphic appearance on low‐power, there was significant pleomorphism and brisk mitotic activity on high‐power examination (Figure 1C) which was reflected by its overall high Ki‐67 proliferation as well. The hyperchromatic tumor nuclei had irregular nuclear membranes. Immunohistochemistry demonstrated a majority of tumor cells to be positive for glial fibrillary acidic protein (GFAP) (Figure 1D), with retained ATRX expression (Figure 1E) and non‐reactivity for p53, mutant IDH1 (R132H) and synaptophysin. FISH studies showed normal dosages of chromosomes 1 and 19 and no evidence of EGFR amplification although there was polysomy of chromosome 7. Loss of PTEN by monosomy of chromosome10/10q was also present (Figure 1F). Additionally, molecular analysis was performed using a next‐generation sequencing platform to analyze a select panel of genes, including IDH1, IDH2, TP53, BRAF, EGFR, PTEN, ATRX, PDGFRA and H3F3. This work‐up revealed mutation in the H3F3 gene because of an amino acid change (K27M) which has frequently been described in pediatric high‐grade gliomas. An immunohistochemical stain for this mutant protein (H3K27M) was also positive in tumor cells in concordance with the sequencing results (Figure 1G). What is your diagnosis?

Diagnosis

Small cell astrocytoma.

Discussion

This is an interesting case of small cell astrocytoma in a child because of the overall rarity of this specific variant and especially so in pediatric population. In adults, these tumors are thought to behave more like primary glioblastoma, particularly when associated with EGFR amplification and/or PTEN/10q loss even in the absence of microvascular proliferation and/or necrosis 4. The clinical behavior of this particular phenotype is however less clear in children although it appears to be equally aggressive from the illustrated example as well as rare reports in the literature 3. Notably, the presence of the H3F3 K27M mutation, as identified in this pediatric high‐grade glioma, is also associated with shorter survival as compared with wild‐type tumors 1, 2. On morphological evaluation, a diagnosis of small cell astrocytoma was favored because of its discrepant findings of relatively uniform nature on low‐power, and significant atypia, and brisk mitotic activity on high‐power examination. An anaplastic oligodendroglioma was nevertheless a close differential diagnostic consideration, prompting further ancillary studies. Findings of monosomy10/10q and polysomy of chromosome 7 without 1p19q co‐deletions were more consistent with a small cell astrocytoma. In summary, this relatively uncommon example of small cell astrocytoma showed molecular features associated with both adult‐type (PTEN/10q loss) and pediatric‐type (H3K27M mutation) high‐grade astrocytoma. Whether or not H3K27M mutation plays any role in rendering astrocytomas with a small cell phenotype a worse prognosis, is rather intriguing and requires further exploration.