Giant cell tumor of the bone (GCTB), an intermediate locally aggressive neoplasm that frequently involves the epiphyseal region of the long bones. GCTB of the distal phalanx and soft-tissue recurrences are extremely rare. Little is known about the cellular and molecular differences between GCTB of the long bones and rare sites.

We employed single-cell RNA sequencing to elucidate the transcriptional profiles of 28,992 cells originating from patients afflicted with GCTB in the femur, distal phalanx, and soft-tissue relapse. To confirm the critical findings, we subjected the paraffin sections of GCTB to immunohistochemical staining.

Our study revealed that GCTBs in rare sites display distinct immune subtypes and antigen presentation gene signatures. We observed minimal lymphocyte infiltration in GCTBs of the phalanx. Further analyses demonstrated that the transforming growth factor-β pathway and profibrotic proteins were significantly upregulated in phalanx lesions. In contrast, GCTB cells from soft-tissue recurrence exhibited discernible chondrocyte characteristics but presented lower antigen-presenting ability compared to those from femur lesions. Notably, we identified an immunosuppressive subset of mast cells in the soft-tissue recurrence. The secretion of proangiogenic and immunosuppressive factors from these mast cells suggests their potential role in the formation of vascular-rich and immunosuppressive niches in recurrent lesions.

Collectively, this study broadens our comprehension of the gene expression patterns observed in infrequent location GCTBs and furnishes a repository of information for illuminating promising therapeutic targets for rare GCTBs.