Case
A 1-year-old female infant was referred to our hospital from a local
hospital due to the detection of a tumor in the left cerebellopontine
angle (CPA) on brain magnetic resonance imaging (MRI). Physical
examination and blood tests revealed no notable abnormal findings,
except for an enlarged head circumference (+2.1SD). The patient also
presented with an intermittent squall for a short period of time, with
lacrimation only from the left eye. Radiologically, the tumor did not
directly interact with the cerebellum but appeared to show continuity
with the left border of the pons (Figure 1). The left trigeminal nerve
was compressed by the tumor (Figure 1). The patient underwent a biopsy
with craniotomy, and the postoperative course was uneventful. The tumor
morphologically consisted mainly of large nodular structures with
well-defined borders and low-to-moderate cell densities within the
nodules. Between the nodules, a dense network of cells with a high
nuclear/cytoplasm ratio and round nuclei with hyperchromatic chromatin
was observed. Silver staining revealed numerous reticular fibers in the
dark background surrounding the bright nodules. The MIB-1 index score
was low at the nodules but high (68%) around the nodules.
Immunohistochemical staining was positive for synaptophysin and NeuN and
negative for GFAP. INI-1 immunoreactivity was retained in all specimens
(Figure 1). Overall, the pathological appearance was very similar to
medulloblastoma with extensive nodularity. Based on the recently-updated
WHO’s classification of central nervous system tumors, an initial
diagnosis of “embryonal tumor, NOS” was made owing to the unusual
tumor location and the lack of evidence of an interaction with the
cerebellum, which is regarded as the origin of a medulloblastoma.
Molecular analysis was performed to elucidate tumor pathogenesis. Based
on expression analysis using NanoString technology, the case was
included into the SHH subgroup with a high confidence value. Using DNA
methylation analysis with the molecular classifier v12.5, developed by
the German Cancer Center, the tumor was also classified as
“Medulloblastoma, SHH-activated” with a substantially calibrated score
of 0.766. A mutation panel sequencing of the tumor revealed a pathogenic
variant of PTEN (c.493G>T:p. Gly165Ter) with a
variant allele frequency of 84.62%.
Subsequent sequencing of normal
tissue confirmed that the variant was a germline mutation, indicating a
diagnosis of Cowden syndrome (Figure 2A). Additionally, copy number
analysis revealed a loss of heterozygosity at 10q, where the PTENwas located (Figure 2B). Altogether, the molecular analyses supported
the classification of the tumor as medulloblastoma despite its atypical
location and no radiological sign of the relationship with the
cerebellum. She underwent four courses of chemotherapy consisting of
cyclophosphamide, etoposide, cisplatin, vincristine, and intrathecal
methotrexate, followed by high-dose chemotherapy with thiotepa and
melphalan, according to the protocol of the Japanese Pediatric Brain
Tumor Consortium2). We performed a second-look surgery
for partial resection of the tumor following high-dose chemotherapy due
to minimal reduction in the size of the lesion, as observed on brain
MRI, even after intensive treatment. The pathological specimen obtained
from the second operation revealed disappearance of the high-cellularity
area among the nodules, and the MIB-1 index was reduced to 5%,
suggesting the cytoreductive effectiveness of chemotherapy. The patient
has remained well without evidence of recurrence for 18 months since the
diagnosis. The periodic squall, initially interpreted as a trigeminal
neuralgia due to nerve compression by the tumor, has persisted with a
mild reduction of the symptoms after administration of carbamazepine.