Case Reports
Case #1
A 9-year-old girl with no significant family history presented with 2 weeks history of persistent headaches, vomiting and abdominal pain. Physical examination at presentation did not show any neurologic deficits nor any stigmata of genetic predisposition. Radiological studies, including magnetic resonance imaging (MRI) of the brain, revealed two space-occupying lesions. The first lesion was located in left fronto-temporal region and displayed high grade features. The second lesion was located in the right cerebellar hemisphere and demonstrated lower grade features than the former lesion (figure 1). MRI of the spine and CSF analysis did not show evidence of metastatic disease. The patient underwent gross total resection of the left parietal tumor and subtotal resection of the right cerebellar tumor. Histopathological examination of the ST tumor showed a highly cellular glial neoplasm with prominent pseudo vascular rosettes and ependymal like cytological features. The neoplastic cells were rather small, containing pleomorphic nuclei, many mitotic figures with apoptotic bodies identified. Following immune-histochemical studies, the tumor cells were immunoreactive with GFAP with absence of Olig2 expression. Ki67 (proliferative index) was very high (80%). There were foci of microvascular proliferation as well as tumor necrosis. Molecular analysis was performed on paraffin embedded tissue and the chromosomal microarray analysis identified multiple genomic alterations in the tumor, including gain of chromosomes 8, 13, and 14, copy neutral loss of heterozygosity (cnLOH) from 9p24.3 to 9p13.3 with focal homozygous deletion of 9p21.3 (including CDKN2A and CDKN2B), cnLOH of chromosome 12 and chromothrypsis of chromosome 11. Next generation sequencing (NGS) identified C11orf95-RELA (exon3:exon2) gene fusion. Final diagnosis was “Anaplastic EPN (WHO Grade III), RELA fusion-positive”. Microscopic examination of the cerebellar tumor demonstrated a different histological pattern. The tumor was localized and far less cellular, and the neoplastic cells were spindle in shape with oval bland nuclei. No definite Rosenthal fibers or eosinophilic granular bodies were observed. There was no significant increase in mitoses, and no necrosis or microvascular proliferation was present. Immunohistochemically, the cells were positive with GFAP and Olig 2; Ki67 ( proliferative index) was low (2-3%). BRAF KIA1549 fusion was not detected. The final diagnosis of a pilocytic astrocytoma (PA), BRAF fusion negative was attained. Next generation sequencing (OncoRisk expanded) panel for 89 genes, including CNVs analysis, was performed to investigate any underlying germline mutation but did not detect any pathogenic variants. Following the surgery, the patient suffered from transient weakness in her right arm and leg which resolved within 2 weeks. She received focal radiation (RT) therapy to the supratentorial tumor at a total cumulative dose of 59.4 Grays in 33 fractions. Upon follow up, three and six and months post radiation therapy, there was complete resolution of the first high grade lesion without evidence of disease recurrence. The second tumor in the posterior fossa showed stable residual disease without significant signs of progression. Later on, at nine months follow up, a new dural based lesion in the left temporal area was detected with radiologic characteristics similar to the initial supratentorial tumor. Tumor resection was not feasible due to marked tumor vascularity and risk of bleeding. Biopsy of the dural based lesion showed similar histological and immunohistochemical findings to that seen in the first high grade supratentorial lesion. The patient received treatment with 5 drug metronomic therapy (bevacizumab, celecoxib, thalidomide, alternating oral etoposide and cyclophosphamide). Tumor response to therapy was remarkable, and gross total resection was feasible after 4 months of uninterrupted therapy. The patient was planned to receive craniospinal radiation therapy following tumor resection; however, she developed severe ventriculitis and remains hospitalized for treatment of the infection. She is currently alive at 19 months from initial diagnosis and remains disease free.
Case #2
A of 12-year old boy presented with right sided focal seizures. His family history was negative for inherited cancers and did not elicit any clinical or radiological stigmata of any genetic predisposition syndrome. The initial MRI of the brain showed two intra axial tumors in different locations: one in the frontal lobe and another one in the cerebellum. They both exhibited similar radiologic features of low grade lesions (figure 2). The family refused any surgical intervention, and he was managed symptomatically with antiepileptic medications and close observation with serial brain MRIs. The condition remained clinically and radiologically stable until five years later when he developed new onset persistent headaches and vomiting. MRI of the brain at that time showed significant increase in the size of the left frontal lobe mass with development of a cystic component and restriction of water diffusion suggestive of MT. The cerebellar lesion did not show significant changes. He underwent subtotal resection of the of the frontal lobe tumor with concurrent biopsy of the cerebellar tumor. Postoperatively, he underwent focal radiotherapy RT to the left frontal lobe lesion at a total cumulative dose of 59.4 Gy with concurrent chemotherapy. Six months later, the left frontal lobe tumor progressed again and he underwent a debulking surgery. He passed away three months after the second surgery. Genetic testing to detect underlying germline mutations was not performed. Histological examination from the first surgical intervention reveals a high grade glioneurnal tumor with calcifications. Immunohistochemical staining showed a mixture of neurons stained with synaptophysin and NSE, while the glial component displayed astrocytic cytological features. There were numerous mitotic figures but no microvascular proliferation or necrosis were present. The diagnosis of an anaplastic ganglioglioma (WHO grade III), negative for 1p36 and 19q deletions. The second lesion in the cerebellar showed all the classical histopathological features of a pilocytic astrocytoma (WHO grade I), negative for BRAF fusion and BRAF V600E mutation.
Tissue from the second surgery revealed a high grade glioneuronal tumor with hyper cellularity and large areas of necrosis. The neoplastic cells had a more epithelioid cell morphology, with numerous giant cells; mitotic figures were easily identified, reaching 9 per 10 high power fields. Proliferative index Ki-67 was 60% and P53 stain was diffusely and strongly positive in 60% of the nuclei. The final diagnosis was glioblastoma (GBM), a giant cell type (WHO grade IV).