A four-year-old female underwent subtotal resection of a right medullary schwannoma. The tumor was identified on magnetic resonance imaging (MRI) obtained for progressive head tilt (Fig. 1). Past medical history was notable for developmental delay and facial asymmetry (hemifacial microsomia). A prior MRI performed at age 18 months showed cerebellar hypoplasia, but no tumor. A comprehensive clinical genetic workup including targeted and whole exome sequencing of the germline was negative. Most recent follow-up MRI of the brain eight months after diagnosis showed stable residual disease.
Histologic examination disclosed a neoplasm composed of monomorphous spindle cells in tight, interlacing fascicles (Fig. 2a), without Verocay bodies or Antoni B areas. Devoid of mitotic activity, tumor cells focally dissected into adjoining neuroparenchyma along blood vessels. Immunohistochemical studies showed the lesion to be rich in collagen IV, with tumor cells being negative for GFAP, EMA and SSTR2A, while expressing S100 protein (cytoplasmic/nuclear) and SOX10 (nuclear).
DNA methylation profiling [4] with the Heidelberg brain tumor classifier version 11b6 revealed a match to the methylation class schwannoma with a calibrated score of 0.97. Paired targeted next-generation sequencing analysis of tumor and matched normal sample [5] was negative for somatic mutations as well as structural variants, and revealed a relatively flat DNA copy number profile with focal genomic gains and losses at chromosome 11q including the YAP1 locus (Fig. 3) [6]. RNA sequencing using Anchored Multiplex PCR [7] revealed an in-frame fusion between exon 5 of YAP1 and exon 2 of MAML2 (Fig. 4). YAP1-MAML2 fusions have been reported in NF2-wild type meningioma [8] and other cancers [9], but not schwannomas. As seen in all N-terminal YAP1 fusions reported to date, the fusion detected in our patient retains the TEAD transcription factor binding domain of YAP1, along with the nuclear localization sequence and transactivation domain of MAML2. The resulting fusion protein is resistant to inhibitory signaling of the Hippo tumor suppressor pathway by constitutive nuclear localization and resistance to proteasomal degradation [10]. In keeping with these observations, we confirmed strong nuclear localization of YAP1, as well as weaker cytoplasmic labelling in our patient’s tumor by immunohistochemistry (Fig. 2b).