HMGA2::NCOR2 fusion-driven giant cell tumors: Diagnosis and treatment

Giant cell-rich tumors encompass a heterogeneous group of bone and soft tissue neoplasms with overlapping morphologic features but distinct molecular drivers and clinical behaviors. Recent studies have identified a unique subset of giant cell-rich tumors characterized by recurrent HMGA2::NCOR2 gene fusions, variably described as xanthogranulomatous epithelial tumor or keratin-positive giant cell tumor. In this paper, we emphasize the clinicopathologic, histologic, and molecular features that distinguish these rare neoplasms from conventional giant cell tumors of bone, soft tissue giant cell tumors, and tenosynovial giant cell tumors. Although these tumors generally exhibit an indolent clinical course, their optimal management remains undefined due to limited published experience. Emerging data suggest signs of therapeutic activity with targeting the CSF1 signaling pathway, and there may be a role for tyrosine kinase inhibitors such as imatinib in selected cases. In contrast, the role of denosumab in this molecularly distinct entity remains unclear. Given the rarity of HMGA2::NCOR2-rearranged tumors, improved recognition and molecular confirmation are essential to refine diagnostic criteria and guide future therapeutic strategies.