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.