Orthopedic surgeon experience, based on clinical follow-up and histopathological data, on osteoclastic inhibitor denosumab pretreatment of giant cell tumor of bone – case presentation

Introduction

Giant cell tumor of bone (GCTB) is a primary osteogenic tumor of the bone, accounting for approximately 20% of benign tumors in the adult population, but it represents less than 5% of all primary bone tumors^(1-3). In 2020, the World Health Organization (WHO) defined GCTB as an intermediate malignant tumor⁽³⁾.

GCTB occurs as a primarily solitary tumor and commonly arises at the meta-epiphyses of long bones (distal femur, proximal tibia), although it can occur at any bony site^(2-4). Initially, tumor expansion begins from local bone structures, with a later possible involvement of the surrounding soft tissues⁽²⁾. Giant cell tumor of bone is regarded as a “rarely metastasizing” entity, according to the WHO classification, usually presenting with locally aggressive features, behaving as a mass progressively enlarging and destroying the bone and, in advanced GTCB, invading the surrounding structures. Distant metastases, mainly pulmonary, are reported in less than 5% of all GCTB cases⁽⁵⁾. Histologically, giant cell tumor of bone consists of two different cellular populations: osteoclast-like multinucleated giant cells expressing RANK, rounded mononuclear histiocytic cells expressing RANK precursor of osteoclasts, and round or ovoid mononuclear stromal cells expressing receptor activator of nuclear factor-kappa beta ligand (RANKL) – which are considered the neoplastic component of the tumor^(5,6).

The pathophysiology of GCTB has been elucidated, with nuclear factor kappa B ligand (RANKL) being identified as a key player. Furthermore, a driver gene mutation in histone H3.3 is characteristic of the giant cell tumor of bone⁽³⁾.

The main treatment modality of GCTB is surgery, which includes extensive curettage with or without adjuvants (denosumab) and en bloc resection, depending on tumor primary site, size, extension and involvement of the surrounding soft tissues^(1,5). En bloc resection is recommended for tumors with far-ranging bone destruction and soft tissue extension. It minimizes the risk of local recurrence, but it correlates with a higher rate of surgical complications and functional impairment⁽¹⁾.

Denosumab is an anti-RANKL monoclonal antibody that inhibits osteolysis, proliferation and activity of osteoclasts, with various uses, including the treatment of osteoporosis in postmenopausal women at high risk of fracture and bone metastases associated with solid tumors⁽³⁾. Denosumab has emerged as an effective treatment for GCTB in unresectable cases or in instances where surgical resection would likely result in severe morbidity. It has led to the reduction of pain, halted bone destruction, and induced tumor regression⁽⁴⁾. Denosumab, which is a fully humanized monoclonal antibody (mAb), binds to and inhibits RANKL, therefore blocking the RANK-RANKL axis, halting the formation of osteoclastic giant cells, and finally dampening the osteolytic process⁽⁴⁾. Three to four doses of neoadjuvant denosumab (at a dose of 120 mg subcutaneously) can be given in patients with advanced GCTB, where denosumab can help facilitate the surgical curettage (convert a lesion needing resection to one that could possibly be treated with curettage) or the en bloc surgical resection of the tumor. Long-term denosumab can be used for surgically unsalvageable GCTB⁽⁶⁾. The ideal dose, duration and frequency that balances disease control against the side effects of long-term treatment have yet to be determined⁽⁶⁾.

Case presentation

A 22-year-old male presented to our hospital with a massive tumoral mass in the proximal anterior left tibia. Imaging examination was performed, with the conventional radiography showing a lytic lesion with ill-defined but non-sclerotic margins, extending to the surrounding soft tissues (Figure 1).

A needle-biopsy was performed and sent to the pathology department, where it was processed for the subsequent histopathological examination. The diagnostic of giant cell tumor of bone was established after IHC testing.

Method. Tumor tissues came from needle-biopsy and surgical sample of the bone tumor, collected in our clinic in accordance with the imaging data. The fresh material was then fixed for 1-3 days in neutral 10% buffered formalin, followed by paraffin embedding procedures. Slides obtained from the paraffin blocks, with 4-µm thick sections, were stained with Hematoxylin & Eosin (HE) after a standard procedure. The immunohistochemistry panel was established after the histopathological aspects correlated with clinical and imaging data. We performed immunohistochemical tests with LEICA BOND III automatic machine, using Leica Bond antibodies for: p63 (7JUL), Tartrate resistant acid phosphatase – TRAP (26E5), CD56 (clone 564), CD34 (QBEnd/10), Ki-67 (clone MM1).

The Hematoxylin & Eosin slides revealed a highly cellular lesion composed of large number of non-neoplastic osteoclast-like giant cells with intercalated mononuclear neoplastic cells. Additional immunohistochemical (IHC) markers showed p63 nuclear positivity in tumoral cells, TRAP positivity in osteoclast-like giant cells, CD56 positivity in tumoral cells as a surrogate for osteoblastic differentiation⁽⁷⁾, CD34 positivity in vessel wall, and proliferation index ki67 positivity in approximately 15% of tumoral cells (Figure 2).

Based on histological and immunohistochemical features, in correlation with clinical and imaging data, it was concluded that the tumor was a giant cell tumor of the bone, with extension in the surrounding soft tissues. Subsequently, the best course of action was considered to be an initial treatment with denosumab, followed by the extensive surgical excision of the tumor and the surrounding soft tissue, and additional prosthesis bone replacement. Given the diagnosis and the disease extent in the soft tissues, the patient was given a preoperative treatment with five doses of denosumab – Xgeva® (120 mg subcutaneously, the first three loading doses administered in the first month, on days 1, 7 and 15, followed by two more doses the following two months, once per month), obtaining a very good response to the treatment, with high calcification and delimitation of the tumor and additional reduction in tumor size. Following the initial treatment with denosumab, the patient underwent surgical resection of the tumor and proximal tibia reconstruction with modular tumor prosthesis and external device reconstruction (Figure 3).

The surgical specimen consisting of the resection of the proximal tibia and fibula was sent to the pathology department for further histological examination. Macroscopically, the specimen was a 11-cm proximal tibia largely ossified and a 6-cm fibula with surrounding soft tissue. Within the bone, there were small soft, friable, yellow slightly brownish islands, somewhat poorly defined, with the surrounding cortex thinned and focally destroyed, with extension of the lesion into the soft tissues. Numerous samples were taken from the surgical specimen and were processed in blocks of paraffin, including the surgical bone resection margins. The H&E revealed substantial tumoral ossification and fibrosis, with osteoclast-like giant cells being present only focally, in a very restricted area (Figure 4).

Discussion

The giant cell tumor of bone (GCTB) is a benign pathologic entity that may harm the joint, as it rises in the epiphyses of the long bones. Therefore, preserving the joint in aggressive GCTB may be sometimes a difficult mission.

Clinical studies have demonstrated the efficacy of denosumab in managing GCTB. Patients treated with denosumab have shown significant reductions in tumor size and improved bone density, which can facilitate less invasive surgical procedures and potentially preserve joint function. Additionally, denosumab has been beneficial in cases where surgery is not feasible due to the tumoral location and regional aggressivity.

Despite these benefits, there is no clear protocol mentioning the use of denosumab before surgery in GCTB (neoadjuvant therapy), in the literature existing different concepts regarding this type of usage.

Thus, in conservative surgical procedures, it is said that using denosumab for more than two months may lead to an inefficient curettage due to the residual tumor cells on the intracavitary walls of the bone lesion. In our experience, this argument is not valid, the recurrence of GCTB occurring related to the grade of the invasion in the subchondral bone of the adjacent joint and probably correlated to a mis-curettage of the walls in such situations.

But in resection surgical procedures followed by joint reconstruction, denosumab showed to be effective in reducing the tumor size and giving consistency to the tumoral margins, helping the surgeon to have a clear delimitation between tumor and the surrounding soft tissues, facilitating the tumoral en bloc resection.

Regarding the aforementioned statement, our protocol is to use five doses of denosumab injections, three every one week in the first month, followed by other two injections, one monthly. At three months, all GCTB cases showed radiological changes regarding margins and tumoral bone density, providing the surgeon a clear field of demarcation between tumor and soft tissue, and helping the oncologic resection of such a bone lesion. This kind of therapeutic guideline was used for:

recurrent GCTB not previously treated with denosumab, but by failed initial surgery;

locally aggressive GCTB with intraarticular involvement and destruction of subchondral bone;

locally aggressive GCTB without clear radiological and imagistic IRM and CT-scan margins, that may not be surgically treated per primam.

Conclusions

The ossification of the GCTB after denosumab is a well-established phenomenon due to the osteoclastic inhibitor action of the drug. We consider that, in specific cases, the neoadjuvant denosumab treatment of the giant cell tumor of bone is helping in providing afterwards a smooth and clear resection of this tumor.

More studies should be done in order to establish the most suitable usage of denosumab in the treatment of aggressive giant cell tumor of bone.   

Corresponding author: Florinel Pop E-mail: florinel.pop@spcaroldavila.ro

Conflict of interest: none declared.

Financial support: none declared.

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