(P 104) INFANTILE EXTRARENAL SPINDLE CELL MESENCHYMAL NEOPLASMS WITH TARGETABLE EGFR KINASE DOMAIN DUPLICATIONS

Objective: Epidermal growth factor (EGFR) kinase domain duplication (KDD) [EGFR-KDD] most commonly occurs in non-small cell lung carcinomas and has recently been described as a driver event in classical histology congenital mesoblastic nephromas (CMN-classical) that are negative for ETV6::NTRK3 fusion. The ETV6::NTRK3 fusion is characteristic of cellular histology congenital mesoblastic nephromas (CMN-cellular). CMN-cellular is histologically and genetically similar to infantile fibrosarcoma, while CMN-classical has histologic and immunophenotypic similarity to infantile myofibroma/myofibromatosis. Here we describe EGFR-KDD in 2 cases of extrarenal infantile spindle cell tumors; 1 case with infantile fibrosarcoma-like histology and 1 case with infantile myofibroma/myofibromatosis-like histology.

Methods: Case 1. A 2 year old male was noted to have scoliosis at a well child check-up. MRI demonstrated a left paraspinal mass in the posterior mediastinum associated with scoliosis of the regional thoracic spine. A needle core biopsy showed a hypercellular neoplasm composed of primitive spindle cells arranged haphazardly or in vague whorls and fascicles embedded in sparse stroma that contained scattered lymphocytes, lymphoid aggregates, and branching thin-walled blood vessels. The histomorphology was compatible with infantile fibrosarcoma.

Case 2. A 36 weeks’ gestation male was noted to have a left leg mass on fetal ultrasound done on the day of delivery. MRI performed after delivery showed a large retroperitoneal mass with inferior extension into the left leg. A needle core biopsy showed a moderately cellular neoplasm composed of spindle cells arranged in intersecting fascicles embedded in a moderate amount of collagenous stroma containing ectatic and branching thin-walled blood vessels. The cells showed patchy immunoreactivity for smooth muscle actin. The histomorphology and immunophenotype were compatible with infantile myofibroma/myofibromatosis.

Targeted RNA sequence analysis for both cases was performed by next generation sequencing (NGS). Total RNA was isolated from formalin fixed/paraffin embedded tumor tissue; library preparation and target enrichment was performed using Archer RNA Fusion v1 Custom FusionPlex® Kit (ArcherDx). This assay targets regions of 93 genes known to be associated with fusions in pediatric neoplasms. NGS was performed on the Illumina MiSeq instrument. The analysis and fusion/variant detection was performed using Archer Unlimited software (ArcherDx).

Results: Case 1. Next generation sequencing identified EGFR-KDD involving exons 18-25. No other fusion events in the targeted genes, including NRK1, NTRK2, NTRK3, or ALK were identified. The patient was started on erlotinib and has shown marked radiologic response with 80% reduction in tumor volume.

Case 2. Next generation sequencing identified EGFR-KDD involving exons 18-25. No other fusion events in the targeted genes, including NRK1, NTRK2, NTRK3, or ALK were identified. The tumor showed partial response to treatment with vinblastine and methotrexate; and is currently being treated with erlotinib.

Conclusion: We describe EGFR-KDD in infantile extrarenal spindle cell mesenchymal neoplasms with histomorphologic overlap with infantile fibrosarcoma (and therefore, CMN-cellular) and infantile myofibroma/myofibromatosis (and therefore, CMN-classical) and therapeutic response to EGFR kinase inhibitor erlotinib. This is the first report of pediatric patients treated with EGFR tyrosine kinase inhibitors for tumors harboring EGFR-KDD.