(P 466) PATHOGENESIS AND THERAPEUTIC TARGETS IN KERATIN-POSITIVE GIANT CELL-RICH TUMOR

Objective: Keratin-positive giant cell-rich tumor (KPGCT) is an extremely rare, newly described tumor arising in bone and soft tissue. The tumor is characterized by keratin-positive cells, sometimes with abundant xanthogranulomatous infiltrate(“xanthogranulomatous epithelial tumor”), and harbors HMGA2::NCOR2 gene fusions. The identity of the cells harboring this translocation is unknown, and little is known about the tumorigenic mechanism of KPGCT. Our study aimed to elucidate the mechanisms by which these tumors develop, and identify possible therapeutic targets.

Methods: Using 10x Genomics single-nuclei sequencing (snRNA-seq) we analyzed 27675 nuclei from a total of five formalin-fixed paraffin-embedded (FFPE) KPGCT cases. snRNA-seq findings were validated using IHC and immunofluorescence on corresponding FFPE cases and independent cases from our archive.

Results: We show that KPGCT consists of a small amount of scattered keratin-positive neoplastic cells that co-express HMGA2 and CSF1. The bulk of the tumor consists of macrophages and osteoclast-like giant cells that express CSF1R. The cells with the HMGA2 translocation show upregulation of the hippo signaling pathway, a pathway that is known to directly regulate CSF1 expression.

Conclusion: While being distinct tumor types, many of the histologic features and pathophysiological mechanisms of KPGCT are similar to those of tenosynovial giant cell tumor (TGCT). One central mechanism is the CSF1-CSF1R axis which is likely stimulating the migration and proliferation of macrophages, as well as their differentiation into osteoclasts. This suggests that newly developed small-molecule CSF1R inhibitors that show high efficacy in TGCT may also be an effective therapy for KPGCT.