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).