(P 15) INTRAOSSEOUS RHABDOMYOSARCOMA OF THE CHEST WITH FUS:TFCP2 FUSION AND GERMLINE VARIANTS IN NF1 AND SBDS: NOVEL LOCATION AND MOLECULAR CHARACTERISTICS OF A RARE TUMOR

Objective: Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma in children and is occasionally associated with cancer predisposition syndromes such as neurofibromatosis type 1 (NF1). Intraosseous rhabdomyosarcoma (IRMS) is a recently introduced, rare subtype of spindle cell RMS that shows predilection for the craniofacial bones of female adolescents and young adults (AYAs) and has a characteristic gene fusion of transcription factor cellular promoter 2 (TFCP2) with Ewing sarcoma RNA binding protein 1 (EWSR1) or fused in sarcoma (FUS). Less commonly, IRMS has been found in the femur and pelvis. Here we present a case of IRMS of the chest wall in an adolescent with NF1 that on imaging was originally thought to be a malignant peripheral nerve sheath tumor. To the best of our knowledge, this is only the second reported case of IRMS of the chest wall, first in an adolescent, and the first reported case of IRMS in NF1.

Methods: Next generation sequencing (NGS) was performed by Caris Life Sciences, which includes tumor whole exome and transcriptome sequencing along with detection of copy number variants, insertions/deletions, loss of heterozygosity, tumor mutational burden, and microsatellite instability. Germline testing was performed by Prevention Genetics NGS and included exome sequencing and copy number variant detection.

Results: A 13-year-old female with NF1 presented with fatigue, right upper extremity pain, and unintentional weight loss. Labs showed leukocytosis, normal hemoglobin, and thrombocytosis. Computed tomography revealed a right upper chest mass (10.5 x 9.9 x 10.3 cm) with extension into the neck and spinal canal, metastatic pulmonary lesions, and pathologic compression fractures of the first and second thoracic vertebrae. Bilateral bone marrow specimens prior to therapy initiation were negative for sarcoma but showed hypocellular marrow. Primary lesion biopsy showed epithelioid and spindle cells immunopositive for desmin, MYOD1, ALK, and H3K27ME3. Fluorescence in situ hybridization revealed FUS rearrangement. Molecular tumor profiling revealed FUS:TFCP2 fusion (FUS exon 6 joined in-frame to TFCP2 exon 2) and pathologic NF1 variant (c.5595dup), confirming IRMS. VAC (vincristine, dactinomycin, cyclophosphamide) therapy was initiated. After two doses of dactinomycin, she developed grade 3 veno-occlusive disease (VOD) of the liver, a rare complication of dactinomycin. She was successfully treated with defibrotide and transitioned to VIE (vincristine, ifosfamide, etoposide) given comparable response and toxicity to VAC in RMS. She developed prolonged cytopenias on VIE, prompting repeat marrow studies, which were hypocellular but remained negative for sarcoma. Inherited bone marrow failure syndrome testing was performed given cytopenias and hypocellular marrow on initial and repeat specimens and showed germline pathogenic/likely pathogenic heterozygous variants in Schwachman-Bodian-Diamond syndrome (SBDS) (c.258+2T>C) and NF1 (c.5595dup). Pancreatic isoenzymes were negative. To the best of our knowledge, she is a carrier but does not have Schwachman-Diamond syndrome. She is still undergoing therapy but has responded well to VIE and radiation, with partial response of the primary lesion and complete response of the metastatic lesions by the Response Evaluation Criteria in Solid Tumors.

Conclusion: This is the first reported case of IRMS in association with NF1 and of the chest wall in an adolescent. Reported cases of RMS and NF1 are almost exclusively embryonal RMS, with coexistence of IRMS and NF1 not previously reported in the literature. Germline pathogenic variants in SBDS were only recently linked to RMS, but have not been reported in conjunction with NF1 variants, and their clinical significance is still uncertain. Our patient’s development of VOD with VAC therapy is uncommon and questions the impact of the collection of these rare genetic variants on therapy tolerability. This case supports the use of molecular tumor profiling paired with germline analysis to better delineate tumor pathology and to begin to understand complicated host biology. Further investigation is warranted into the clinical significance of the heterozygous SBDS variant in relation to NF1, RMS susceptibility, and risk of toxicity with chemotherapeutic agents commonly used to treat RMS.