Giant cell tumor of bone (GCTB) is a relatively rare, locally aggressive benign osteolytic tumor that most commonly affects young adults. GCTB accounts for 4–10% of all biopsy-analyzed primary bone tumors (1–3).

The majority of lesions (85%) develop at the epiphyses of long bones, but may also occur in the sacrum, vertebral body and occasionally in the small bones of the hands and feet (4). In a small number of cases (1–4%), pulmonary metastasis has been reported (5,6). Spontaneous transformation to an overt malignancy occurs in <10% of cases (2,3).

The most common symptoms of GCTB include pain, swelling, impaired mobility of the joints, pathological fractures of involved bones and deformation of the bone (2–4). On radiography, GCTB most commonly presents as a nonsclerotic, osteolytic lesion with clearly defined margins. In addition, pathological fractures located in the metaphysis of long bones that extend to the epiphysis in the subarticular region are common (3,7).

Core needle biopsy, open biopsy or intra-operative frozen section analysis are performed to establish the final diagnosis prior to or during surgery, due to the aggressive nature of the tumor and its tendency for malignant transformation (8–10). Microscopically, GCTB is composed of neoplastic and reactive cell populations. The cell population is composed of osteoclast-like multinucleated giant cells, rounded mononuclear histiocytic cells and round/ovoid mononuclear stromal cells, which represent the proliferative neoplastic component (8,11–13). The stromal cells grow in a syncytium, exhibit ill-defined cell borders with little eosinophilic cytoplasm and variable degrees of mitotic activity. Foci of necrosis and vascular invasion may also be present. Tumors may demonstrate benign fibrous histiocytoma-like areas, hemosiderin deposits, secondary aneurysmal bone cyst changes (10–15% of tumors) and reactive bone formation (6,9,11,14).

Regarding the functional molecular biology of GCTB, receptor activator of nuclear factor-κB ligand (RANKL) is highly expressed by neoplastic mononuclear mesenchymal stromal cells (15–17), whereas RANK is expressed on osteoclast-like cells, which are recruited secondarily in the tumor, but are responsive to the aggressive osteolytic activity (2). RANK-RANKL interactions, which are involved in normal bone formation and function, and macrophage colony-stimulating factor exhibit important functions in osteoclastogenesis by stimulating the recruitment of osteoclastic cells from blood-born mononuclear osteoclast precursor cells that differentiate into multinucleated osteoclast-like giant cells (12,18–20). This is supported by the observation that giant cells in GCTB exhibit an osteoclast-like phenotype. Thus, these consistent findings confirm the involvement of imbalanced RANKL and RANK expression and dysregulation of the RANKL-RANK-osteoprotegerin signaling pathway in the pathogenesis of GCTB and induction of bone over-resorption at the tumor site.

A recent study identified the driver H3F3A gene mutation in 92% of GCTBs, which occurred exclusively in stromal cells (21).

Primary malignancy in GCTB is observed at initial diagnosis as an area of morphologically distinct malignant mesenchymal tumor cells within an otherwise conventional GCTB. In secondary malignant GCTB, sarcomas arise subsequent to previous radiation or surgical treatment and the pre-existing GCTB is not always evident (8,11).

One study hypothesized that the histological features of GCTB indicate subsequent behavior and thus may predict prognosis while providing valuable guidance in treatment (22). GCTB is classified into 3 types: Grade I, tumors exhibit sparse stroma and giant cells predominate; Grade II (atypical/borderline GCTB, identified using H3F3A mutation testing), tumors composed of a smaller giant cell population with atypical cells or single atypical mitoses in the more pronounced stroma; Grade III, tumors represent overt malignant sarcoma (occasionally low-grade) (22). This grading system primarily shows continuum between histologically benign and sarcomatous tumors, underscoring the presence of borderline lesions, which have worrisome features at imaging examinations, but provided they have a positive H3F3A mutation status, still respond well to denosumab treatment. The majority of GCTB cases are classified as grade I, however, ≤20% of cases, even in the absence of histological malignant traits, invade the cortex and directly extend into adjacent soft tissues. This results in major discrepancies between histological tumor grade and radiological stage (23). Radiological staging is considered more important than histological grading for predicting the clinical behavior of GCTB, including recurrence and metastatic potential (2,5,7).

It is also difficult to differentiate GCTB from other mimicking benign bone lesions, such as aneurysmal bone cyst, giant cell reparative granuloma, brown tumor of hyperparathyroidism, benign fibrous histiocytoma or chondroblastoma, as well as malignant lesions, such as giant cell rich or teleangiectatic osteosarcoma and undifferentiated pleomorphic sarcoma (24).

The primary treatment for GCTB is surgery, however local recurrence or metastasis may occur. The type of surgical treatment selected depends on the feasibility of curettage compared with resection and the risk of local recurrence. The most common surgical treatment is local curettage, which exhibits varying rates of local recurrence depending on the use of local adjuvants such as phenol, liquid nitrogen and polymethylmethacrylate cement, described as improved (12–27% of local recurrence) compared with local controls. If local adjuvants are not utilized, the mean recurrence rate is higher (21–65%) (2,7). Furthermore, the risk of local recurrence is markedly increased by soft tissue extension (20–25% of all GCTBs) (7,25). More aggressive forms of surgical treatment, such as en bloc wide resection, may potentially decrease the risk of local recurrence (3), however, this procedure may lead to reconstruction problems and impaired functional anatomy. Prosthesis may be used for local treatment, which results in a good quality of life, however, the risk of local recurrence following this procedure is unclear, and possible complications, particularly in relatively young patients affected by GCTB, must be considered when planning therapy (26,27). En bloc resection should be considered in cases of multiple recurrent GCTB, impossible joint salvage, extensive cortex destruction (insufficient cortex left to curette) and extensive soft tissue involvement (2,7).

Moderate-dose radiotherapy (40–55 Gy) has previously been demonstrated as an effective primary treatment in unresectable GCTB and in cases of residual or recurrent disease whereby surgery would result in unacceptable morbidity, however, with the introduction of RANKL inhibitors this must be redefined and limited to individualized cases. In addition, the risk of malignant transformation after radiotherapy is 0–5% (3).

Bisphosphonates and interferon-α have also been used in GCTB treatment. Bisphosphonates inhibit osteoclast activity and promote their apoptosis, which prevents bone resorption. A previous case study reported that biphosphonate treatment reduced the local recurrence rate of GCTB from 30% in the control group to 4.2% in the bisphosphonates-treated group (28).

Recently, the RANKL inhibitor, denosumab, has been investigated as a treatment for advanced GCTB (1,29). Denosumab is a human monoclonal antibody that binds to RANKL and prevents RANKL activation, thereby inhibiting the maturation of osteoclasts (29,30). The high efficiency of GCTB denosumab treatment has been confirmed in two phase II studies. An open-label phase II study reported an objective response to denosumab therapy in 86% of patients, whereby an objective response was defined as >90% elimination of giant cells on histopathological evaluation or no radiographical progression of the lesion (31). A second, larger study revealed that 96% of surgically unsalvageable GCTB patients exhibited no disease progression during treatment (median follow-up time, 13 months) and acceptable drug toxicity (31–33). Denosumab treatment should be continued until radical resection of the tumor is possible or progression or unacceptable toxicity has occurred.

The present study is the largest single center analysis of denosumab treatment in GCTB patients used in routine practice to date.

The present study summarized the results of denosumab treatment in 35 locally advanced GCTB patients without participation in clinical trials. The results revealed that denosumab exhibits high efficacy with long term responses. This study comprises the largest study of locally advanced GCTB patients without metastasis to receive denosumab in routine practice, and in ≥50% of patients denosumab was administered as a preoperative modality combined with radical local surgery. No patients received denosumab as adjuvant therapy. The primary treatment for GCTB is surgery and the most important challenge in surgical management is the relatively high recurrence rate after curettage (21–65%) (2,7). Two patients exhibited disease recurrence after curettage, which raises significant concerns regarding curettage after denosumab treatment as the recurrence rate was high (6.33%). This indicates that if intralesional surgery is planned after neoadjuvant denosumab, denosumab therapy should be administered for a relatively short period of time (~3 months) as the calcified rim of the tumor may be too thick following 3 months of denosumab treatment, which would prevent radical curettage of the tumor cells. However, a different situation arises in cases whereby wide radical surgery is planned after denosumab therapy. In the present study, prosthetic replacement was performed in 10/17 cases that underwent surgery as the patients exhibited locally advanced tumors, penetration to the joint or pathological fractures. In such situations calcification of tumors that initially penetrate the soft tissues after denosumab therapy may facilitate or enable radical tumor resection with a low risk of tumor recurrence. Therefore, we postulate that in cases where en bloc resection is planned neoadjuvant therapy should be administered for a longer duration to allow maximal calcification of the tumor (Figs. 4 and 5) and response plateau observed on control imaging. Whether denosumab maintenance is required after radical surgery remains unclear, however, in the present study, no disease recurrence was observed.

A phase II clinical trial assessed 222 patients for possible downstaging with denosumab for planned surgery (35). The majority of patients received adjuvant denosumab for 6 months after surgery. Of the 116 patients who underwent surgery (median postsurgical follow-up time, 13 months), local recurrence occurred in 17 (15%) patients, however, by contrast to the present study, the majority of these patients underwent intralesional curettage.

Furthermore, a number of patients present with inoperable GCTB and thus require life-long denosumab treatment. Although good tolerance of treatment has been reported previously (33,31), data regarding long-term use of denosumab for metastatic/inoperable GCTB is limited. It may be possible to reduce the dose frequency (e.g., to once every 3 months) in patients who have achieved long-term stable disease on monthly denosumab (36).

In conclusion, denosumab therapy in GCTB is associated with a high rate of tumor response with a good toxicity profile. The results of the present study confirmed that denosumab exhibits excellent efficacy and short-term tolerability. For patients with advanced, unresectable, progressive, or symptomatic heavily pretreated GCTB, denosumab provides a therapeutic option not previously available and thus, has become the standard therapy for multidisciplinary management of advanced/high-risk or unresectable GCTB. Furthermore, the results of the study data suggest that neoadjuvant therapy with denosumab may present a therapeutic option for patients with locally advanced, high-risk tumors to facilitate complete surgical resection or avoid damaging surgery, however, the risk of recurrence after curettage of GCTB following denosumab therapy raises questions regarding the optimal preoperative duration of treatment. This study confirmed the efficacy of denosumab in 35 patients with locally advanced GCTB treated without participation in clinical trials. Complete tumor resection was feasible in 50% of patients. Therefore, denosumab became the standard therapy for the multidisciplinary management of GCTB.