Giant cell tumor of bone (GCTB) was first described in 1818. GCTB is considered benign, although it is locally aggressive and has the potential to metastasize in its benign form, paradoxically referred to as benign metastasizing giant cell tumor (GCT). Adding to the confusion, there is a rare malignant variant of GCT, which is clinically and histologically distinct. Cases of malignant transformation are most commonly reported following radiation, although recent cases following denosumab therapy have occurred. With advances in diagnostic imaging and understanding of tumor biology, the evaluation and treatment of GCTB has evolved. Much has been learned about the behavior of GCTB via cellular pathways, leading to targeted medical therapy.

GCTB accounts for 5% of primary bone tumors and 20% of all benign bone tumors in North America. In Asia, where the reported incidence of GCTB is higher, it accounts for 13% to 20% of all primary bone tumors.¹ GCTB has a slightly higher female-to-male preponderance. The peak incidence of occurrence is between the third and fourth decades of life. GCTB has been identified and reported in almost every bone of the appendicular and axial skeleton, with a predilection for the metaphyseal-epiphyseal region of long bones. The most common location of GCTB is around the knee, occurring most frequently in the distal femur, followed by the proximal tibia and the distal radius² (Figure 1). Benign GCTB has been observed to metastasize to the lungs in 3% to 5% of cases. GCTB in skeletally immature patients is uncommon, and other diagnostic considerations in this patient population should include solid variant of aneurysmal bone cyst or giant cell-rich osteosarcoma.

The chief report of patients with GCTB is pain that often begins insidiously, with reports of a dull ache that gradually increases over time. As pain increases, the patient may notice swelling of the adjacent joint, soft-tissue fullness, and even a soft-tissue mass overlying the area of concern. A painful limp associated with weight-bearing activities may accompany these progressively worsening symptoms. The patient may relate symptom onset to a trauma. Approximately 20% of patients will present with pathologic fracture,³ usually preceded by prodromal symptoms of pain and decreased motion (Figure 2). GCT of the spine can present with radicular symptoms.⁴

After a detailed history and physical examination, plain radiographs of the affected bone should be obtained. GCTB is typically described as a radiolucent metaphyseal-epiphyseal lesion, most commonly without sclerosis (80% to 85%). The lesion can be quite large and encompass the metaphysis and epiphysis adjacent to the subchondral bone (Figure 3). Cortical erosion and periosteal elevation with expansion of the cortex can also be seen. Radiographs can be stratified according to the Campanacci system:⁵ grade I tumors have a well-marginated border of a thin rim of mature bone, and the cortex is intact; grade II tumors have a relatively well-defined margin but no radiopaque rim; and grade III tumors have indistinct borders and cortical destruction. GCTB most commonly presents as grade II or III.

After plain radiography, MRI is the imaging modality of choice for diagnosis and surgical planning. T1-weighted MRI demonstrates a low-to-intermediate signal, homogenous in most lesions. T2 sequences show heterogeneity because the hemosiderin produces a lower signal and the high water content produces a high signal. Gadolinium-enhanced images confirm a solid lesion with enhancement throughout. MRI details the marrow replacement by the lesion, particularly with regard to the extension to the articular surface of the adjacent joint (Figure 4). MRI can also reveal any extraosseous soft-tissue extension or heterogeneity, suggesting a potentially more aggressive process.

CT can also be used in select cases to evaluate for cortical erosions or sclerosis around the tumor-bone interface, intralesional matrix, joint involvement, or fracture. A thin sclerotic border is often seen on CT, which helps distinguish GCTB from malignancies. Meanwhile, the absence of a thick sclerotic border helps to differentiate this lesion from more indolent lesions. The absence of any significant matrix or mineralization pattern within the tumor helps exclude cartilage tumors and other matrix-producing lesions (Figure 5). Occasionally, GCTB will appear multiloculated on CT (or MRI), usually because of osseous ridges and trabecular remnants left behind from areas of bone that have been removed by osteoclast resorption. The observation of these multiloculated cavities may also suggest the presence of a secondary aneurysmal bone cyst, which occurs in 14% of cases.⁶

Bone scan is useful to detect other sites of skeletal disease, especially in the rare event of multicentric GCT. Radiography or CT of the chest is indicated to evaluate for pulmonary metastases. Positron emission tomography (PET)-CT is an evolving imaging modality for bone lesions. 2-Deoxy-2-[¹⁸F]fluoro-D-glucose PET scans have been successfully used to assess the effectiveness of denosumab treatment in patients with GCTB,⁷ and there is a potential role for PET to help evaluate for malignant conversion of a GCT. However, the exact utility of PET in GCTB remains undefined.

Although the pathogenesis of GCTB has not been fully appreciated to date, several mechanisms of aberrant osteoclastogenesis are now partly understood. GCTB is composed of three cell types: precursor monocytes, osteoclastlike multinucleated giant cells, and neoplastic fibroblastlike stromal cells.⁸ The giant cells are interspersed among the mononuclear precursors and the stromal cells (Figure 6). The nuclei of the giant cells, when compared with the stromal cells, are very similar in size and appearance; both the stromal cells and the nuclei of the giant cells take on round, ovoid, and even polygonal forms (Figure 7). Mitotic activity can be plentiful, and it is not uncommon to see scarce osteoid production. The presence of giant cells alone does not singularly make the diagnosis. The differential diagnosis for a giant cell-rich lesion is extensive and includes tumors such as giant cell-rich osteosarcoma, chondroblastoma, and aneurysmal bone cyst. For this reason, molecular pathology is being increasingly used to confirm diagnosis.

Bone destruction in GCT is mediated by the multinucleated osteoclastlike giant cells, and the receptor activator of nuclear factor kappa-B ligand (RANKL) pathway plays a critical role in regulating this osteoclastogenesis. The stromal cells overexpress RANKL, which stimulate the precursor monocytes to become osteoclastlike giant cells. This action, combined with cytokine secretion by the tumor cells, leads to an autocrine loop of overresorption of bone and the resultant bone destruction seen in GCTB^9,10 (Figure 8).

In addition to RANKL expression, recent advances have also demonstrated that the neoplastic stromal cells in GCTB harbor G34W or G34L mutations of the H3F3A gene in more than 90% of cases.¹¹ This H3F3A mutation is being increasingly recognized as a driving mutation for GCT. Other molecular pathways involved in the complex interplay among the cells seen in GCT are being actively investigated (Figure 9). Identification of these pathways can be of both diagnostic and potentially therapeutic value. For example, H3.3 G34W mutation-specific immunohistochemistry antibody has been shown in recent studies to be a reliable and specific marker for GCTB and can distinguish it from other giant cell-containing tumors.^12,13

PD-L1 expression has also been identified in some cases of GCTB, with early evidence in recent studies suggesting higher recurrence risks in patients with PD-L1-expressing GCTB.^14,15,16 The diagnostic and therapeutic implications of PD-L1 in GCTB need further investigation.

The management of GCTB has evolved considerably over the past several decades, yet controversy still exists regarding the optimal treatment. Options range from intralesional curettage with or without adjuvant to en bloc resection. Treatment historically was simple curettage of the cavitary lesion. This method provided suboptimal results, with high local recurrence rates in the order of 25% to 65%; therefore, the aggressiveness of local treatment has increased. Wide en bloc resection has been shown to result in the lowest recurrence rate but inferior functional outcomes.^1,17,18 As such, resection of GCTB is generally reserved for locations in expendable bones (eg, fibula) or cases not amenable to curettage (Figure 10).

Extended intralesional curettage, which involves the use of a high-speed burr to remove tumor beyond the area of curettage, is the most commonly performed surgical treatment for GCTB. Visualization of the entire defect through a cortical fenestration optimizes the opportunity for complete removal (Figure 11). With this added mechanical adjunct, there appears to be improvement in local recurrence, with recent series reporting rates of approximately 20% with aggressive curettage and high-speed burring.¹⁹

The challenge of adequate local control and morbidity of large resections in this patient population ushered in the era of local adjuvant treatments, which broadly fall under the categories of thermal, chemical, and biologic adjuvants. The theory behind the cavitary adjuvants is that the zone of tumor kill is extended beyond what has been physically removed, without removal of additional structural elements. The depth of necrosis produced by these adjuvants varies, with a general range from 0.75 to 12 mm, depending on the method.²⁰

Thermal adjuvants may be used on the tumor cavity following removal of all gross tumors. Cryotherapy with liquid nitrogen poured directly into tumor cavities has been performed. The relatively uncontrolled extension of the freeze zone with the pour technique can be improved with utilization of thermal probes, providing considerably more control of the cooling mechanism and intraoperative ease of use. Tissue necrosis and postoperative pathologic fracture after treatment remain concerns.