Targeting the colony-stimulating factor 1 axis for the treatment of Tenosynovial Giant Cell Tumors

Diffuse and Localized Tenosynovial Giant Cell Tumors (D-/L-TGCT) are two closely related forms of benign tumors of the joint characterized by uncontrolled macrophage infiltration and proliferation. Both forms arise from similar translocation events in synovial fibroblasts involving the Colony Stimulating Factor 1 (CSF1) gene, the major regulator of myeloid cell survival and activity. This review first describes CSF1 gene structure and protein expression as well as signaling through its receptor (CSF1R). Then, genetic alterations observed in TGCT patients are described in depth. The main features are translocations that remove the 3' regulatory elements of CSF1 messenger RNA, driving its overexpression and the abnormal recruitment of non neoplastic macrophages leading to tumor growth. This review then focuses on the resulting histopathological features characterizing the disease, as well as the available treatments targeting the CSF1 axis. Systemic therapies targeting CSF1 or its receptor are valuable for relapsing or inoperable cases, especially D-TGCT, but their use is still limited by heavy side effects and unresponsive tumors. Overall, our understanding of the pathophysiology of these tumors, the efficacy and limitations of current therapeutic options, and the questions that remain unanswered open new avenues for research and provide opportunities to further improve patient care.