Identification and characterization of neoplastic cells in keratin-positive giant cell-rich tumors.

Authors

Maarten van der Linde, John S A Chrisinger, Elizabeth G Demicco, Carina A Dehner, Gregory W Charville, Inge H Briaire-de Bruijn, Sushama Varma, ChunFang Zhu, Magdalena Matusiak, Judith V M G Bovée, Matt van de Rijn, David Gp van IJzendoorn

Published in

Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 43. Pages e2611959123. Oct 27, 2026. Epub Oct 19, 2026.

Abstract

Keratin-positive giant cell-rich tumor (KPGCT) is a newly described bone and soft tissue tumor. The tumor is characterized by scattered keratin-positive cells and the presence of HMGA2::NCOR2 fusions. It is not known if the HMGA2::NCOR2 fusion is located in the keratin-positive cells, and little is known about how KPGCT develops. KPGCT shares some histologic features with tenosynovial giant cell tumor (TGCT), a soft tissue tumor with CSF1 rearrangements. Single-nuclei RNA sequencing and Xenium spatial transcriptomics were used to elucidate the most likely mechanisms driving KPGCT and compare KPGCT to TGCT. We identified a population of cells coexpressing keratin, HMGA2, and CSF1 as the likely neoplastic cells; these cells constitute the minority of the cells in the tumor. These cells express no synovial markers, confirming KPGCT as a distinct entity, separate from TGCT. The bulk of the tumor consists of CSF1R-expressing macrophages and multinucleated giant cells (MNGCs), suggesting an important role for CSF1-CSF1R signaling. In addition, we find that the likely neoplastic cell population shows activation of the hippo signaling pathway, a possible central pathway in KPGCT tumorigenesis. The CSF1-CSF1R axis likely stimulates the migration and proliferation of macrophages, which form the majority of cells in the tumor, as well as their differentiation into MNGCs. These results provide a rationale for the use of CSF1R inhibitors, which have already shown efficacy in TGCT, as a therapy for KPGCT.

PMID:
42896059
Bibliographic data and abstract were imported from PubMed on 20 Oct 2026.

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