The clinical approach toward giant cell tumor of bone

Abstract

We provide an overview of imaging, histopathology, genetics, and multidisciplinary treatment of giant cell tumor of bone (GCTB), an intermediate, locally aggressive but rarely metastasizing tumor. Overexpression of receptor activator of nuclear factor κB ligand (RANKL) by mononuclear neoplastic stromal cells promotes recruitment of numerous reactive multinucleated giant cells. Conventional radiographs show a typical eccentric lytic lesion, mostly located in the meta-epiphyseal area of long bones. GCTB may also arise in the axial skeleton and very occasionally in the small bones of hands and feet. Magnetic resonance imaging is necessary to evaluate the extent of GCTB within bone and surrounding soft tissues to plan a surgical approach. Curettage with local adjuvants is the preferred treatment. Recurrence rates after curettage with phenol and polymethylmethacrylate (PMMA; 8%-27%) or cryosurgery and PMMA (0%-20%) are comparable. Resection is indicated when joint salvage is not feasible (e.g., intra-articular fracture with soft tissue component). Denosumab (RANKL inhibitor) blocks and bisphosphonates inhibit GCTB-derived osteoclast resorption. With bisphosphonates, stabilization of local and metastatic disease has been reported, although level of evidence was low. Denosumab has been studied to a larger extent and seems to be effective in facilitating intralesional surgery after therapy. Denosumab was recently registered for unresectable disease. Moderate-dose radiotherapy (40-55 Gy) is restricted to rare cases in which surgery would lead to unacceptable morbidity and RANKL inhibitors are contraindicated or unavailable.

Keywords: Curettage; Denosumab; GCTB; Giant cell tumor of bone; Histopathology; RANK ligand; Radiotherapy; Review.

Figure 1.

Radiological appearance of giant cell tumor of bone of distal femur. (A, B): Radiographs demonstrating an eccentric, sharply demarcated lytic lesion in the distal femur metaphysis extending to the epiphysis without tumor mineralization. Radiographic features are consistent with giant cell tumor of bone.

Figure 2.

Pre- and post-denosumab radiological appearance of giant cell tumor of bone of proximal radius. (A, B): Radiographs of a large, expansile, completely osteolytic lesion in the proximal radius demonstrating a permeative destruction pattern with cortical destruction, consistent with giant cell tumor of bone. (C, D): Radiographs demonstrate new bone formation with reconstitution of cortical bone after 5 months of treatment with denosumab.

Figure 3.

Giant cell tumor of bone appearance on magnetic resonance imaging (MRI). (A): T1-weighted MRI demonstrates an eccentric lesion with mild expansion with intermediate signal intensity. (B): T2-weighted MRI shows low signal intensity through hemosiderin depositions and high signal intensity through secondary cystic changes. (C): T1-weighted MRI with fat suppression after intravenous gadolinium administration demonstrates marked, relatively homogeneous enhancement.

Figure 4.

Different radiological modalities in the diagnosis of giant cell tumor of bone. (A): Plain radiograph shows a lytic lesion with extensive cortical destruction and a pathologic fracture in the distal radius. (B–D): T1- and T2-weighted magnetic resonance imaging (MRI) shows inhomogeneous low to high signal intensity and marked enhancement after gadolinium administration. (E–H): Dynamic contrast-enhanced MRI (DCE-MRI) shows homogeneous enhancement within 6 seconds after gadolinium administration. DCE-MRI can provide functional information on tumor angiogenesis and permeability but will not be part of standard imaging protocols in many centers.

Figure 5.

Pre- and post-denosumab histological appearance of giant cell tumor of bone and mechanism of action of denosumab and bisphosphonates. (A): Biopsy with numerous, uniformly spaced, multinucleated giant cells and mononuclear stromal cells. (B): Surgical specimen after denosumab shows stromal cells, scattered mononuclear spindle cells without evident atypia, and diffuse foamy macrophages; no multinucleated giant cells are seen. (C): Mechanism of action of receptor activator of nuclear factor κB ligand inhibitors and bisphosphonates.

Figure 6.

Multidisciplinary treatment recommendations for GCTB. ∗, With extra-articular pathologic fractures, preoperative fracture healing may be delayed, whereas immediate surgery is required with intra-articular pathologic fractures. ∗∗, Caution is warranted with local adjuvants (e.g., phenol, alcohol, liquid nitrogen) in case of involvement of soft tissues or neurovascular structures because it may induce (severe) necrosis. Abbreviations: GCTB, giant cell tumor of bone; MR, magnetic resonance.