Abstract
Soft tissue sarcomas in neonates are rare and heterogeneous tumors. We report an aggressive neonatal undifferentiated round cell sarcoma with a YWHAE:NUTM2B fusion. The tumor was identified antenatally and the neonate underwent surgical resection at four days of age. Whole-genome and transcriptome sequencing of tumour and germline was undertaken to provide molecular characterization and elucidate possible novel therapies. In addition to molecular characterization of a YWHAE:NUTM2B fusion, RNA expression outliers were described. Targeted therapy was not pursued due to rapid clinical decline. Understanding the genomic profile of rare tumors remains important in the development of novel therapeutic strategies.
Introduction
Malignancies diagnosed in the neonatal period are rare and account for 2% of pediatric cancers.1,2 Soft tissue sarcomas comprise 8-12% of all neonatal malignancies, with rhabdomyosarcoma being the most common histologic subtype (32.8%), followed by infantile fibrosarcoma (24.5%) and malignant rhabdoid tumor (14.2%).3–5 Other neonatal non-rhabdomyosarcoma soft tissue sarcomas are less frequent.3 We report a case of a neonate with a congenital undifferentiated round cell sarcoma (URCS) with an underlying YWHAE:NUTM2B fusion who had whole genome transcriptome analysis (WGTA) of tumour performed to characterize its molecular features. YWHAE:NUTM2B is a rare fusion gene described in pediatric clear cell sarcoma of the kidney (CCSK) and adult endometrial stromal tumours6,7, but only three cases have been identified in URCS of infancy. These cases demonstrated aggressive behavior where two of three infants died within months of birth.8,9
Clinical History
A newborn male was delivered by elective caesarian section for a large back mass initially identified on routine antenatal ultrasound. Family history was non-contributory. Postnatal ultrasound showed a 13.0 cm exophytic soft tissue mass along the left upper back with features uncharacteristic of a vascular malformation or hemangioma. Magnetic resonance imaging (MRI) performed one day post-birth showed the mass arising from the left posterolateral chest wall with signal characteristics suggestive of intermixed enhancing vascular and fibrous or hemorrhagic tissue. A near total-surgical resection was performed four days post-birth with positive margins and lymphovascular invasion (Fig. 1).Whole-body MRI did not highlight distant metastatic disease. The family was offered adjuvant chemotherapy but opted for observation only, recognizing the likely poor prognosis. The infant developed distant metastasis and recurrence at the primary site, prompting two doses of Vincristine and one dose of Dactinomycin with no clinical response. Chemotherapy was ceased and supportive care was provided until his death from disseminated disease at 5 months-old. Post-mortem whole-body MRI (in lieu of an autopsy at the family’s request) showed widespread metastatic disease, including tumor burden in the posterior fossa obstructing the ventricular system.
Methods
For full methodology, see Supplemental Information. Histologic slides were prepared by standard techniques and immunohistochemistry performed on a Ventana BenchMark XT Autostainer. DNA and RNA sequencing was performed on frozen tumour tissue (DNA and RNA) and peripheral blood (DNA-only) using the MGISEQ-2000RS Sequencer. Bioinformatic analysis was performed using methods previously described by our group.10
Results