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