Denosumab-treated giant cell tumor of bone. Its histologic spectrum and potential diagnostic pitfalls.

Giant cell tumor (GCT) of bone is a locally aggressive, rarely metastasizing primary bone neoplasm that occurs most frequently in the epiphysis of long bones of young adults. It is composed of round, oval, or elongated mononuclear cells admixed with osteoclast-like giant cells that express receptor activator of nuclear factor κB (RANK). The mononuclear stromal cells express RANK ligand, a mediator of osteoclast activation. Denosumab, a monoclonal antibody that reduces tumor associated bone lysis by inhibiting the action of RANK ligand, has been used to treat selected cases of GCT. We reviewed the clinical records and histologic slides of 9 patients with GCT who had received denosumab therapy and were subsequently surgically treated. There were 5 men and 4 women aged 20 to 66 years (mean, 36 years). Duration of treatment varied from 2.5 to 13months (mean, 5.9 months). In all cases, different degrees of ossification, fibrosis, depletion of giant cells, and proliferation of mononuclear cells were seen. With this combination of changes, denosumab-treated GCT may mimic other lesions such as fibrous dysplasia, juvenile ossifying fibroma, nonossifying fibroma, and osteoblastoma. Less frequent but more relevant is the presence of cellular atypia or patterns of ossification that resemble an undifferentiated pleomorphic sarcoma, a conventional osteosarcoma, or a low-grade central osteosarcoma. The presence of clinical and radiologic response to denosumab, along with the lack of high mitotic activity, atypical mitotic figures, extensive necrosis, or a permeative pattern of growth, represents clues to achieve a correct diagnosis.