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Background Giant cell tumor of bone (GCTB) is a rare osteoclastogenic stromal tumor. GCTB can rarely undergo malignant transformation. This post hoc analysis evaluated and classified malignancies in patients with GCTB who received denosumab. Methods This analysis was conducted on patients with pathologically confirmed GCTB and measurable active disease treated with denosumab 120 mg subcutaneously once every 4 weeks, with loading doses on study days 8 and 15, as part of a phase 2, open-label, multicenter study. We identified potential cases of malignancy related to GCTB through an independent multidisciplinary review or medical history, associated imaging or histopathologic reports, and disease course. The findings were summarized and no statistical analysis was performed. Results Twenty of five hundred twenty-six patients (3.8%) who received at least one dose of denosumab were misdiagnosed with GCTB that was later discovered to be malignancies: five primary malignant GCTB, five secondary malignant GCTB, four sarcomatous transformations, and six patients with other malignancies (giant cell-rich osteosarcoma, undifferentiated pleomorphic sarcoma, spindle cell sarcoma, osteogenic sarcoma, phosphaturic mesenchymal tumor of mixed connective tissue type, and fibrosarcoma/malignant fibrous histiocytoma). Many malignancies were present before denosumab was initiated (8 definitive cases, 7 likely cases), excluding potential involvement of denosumab in these cases. Signs associated with potential misdiagnoses of GCTB included poor mineralization with denosumab treatment, rapid relapse in pain, or a failure of the typical dramatic improvement in pain normally observed with denosumab. Conclusions Although rare, GCTB can undergo malignant transformation, and rates in this study were consistent with previous reports. Signs of poor mineralization or lack of response to denosumab treatment may warrant close monitoring. Trial registration clinicaltrials.gov , ( NCT00680992 ). Registered May 20, 2008.

Background Advancements in diagnostic and therapeutic modalities for giant cell tumors of bone (GCTB) have introduced molecular and radiological tools that refine clinical decision-making. H3.3 G34W immunohistochemical staining has become a routine diagnostic marker, while H3F3A mutational analysis enhances prognostic insights. Treatment primarily involves surgical methods such as curettage or en bloc resection, with denosumab serving as an adjunct in high-risk or inoperable cases. Methods We retrospectively analyzed 55 patients with GCTB, focusing on clinicopathologic and radiological findings. Tumors were evaluated using the Campanacci grading system. Immunohistochemical analysis with H3.3 G34W antibody and next-generation sequencing (NGS) were performed to detect H3F3A mutations. A subgroup of nine patients treated with denosumab was further analyzed for clinical outcomes and histological changes. Results The cohort had a mean age of 37.7 years, with tumors most commonly affecting the knee joint (55%). All tested tumors demonstrated positive H3.3 G34W staining, with eight exhibiting H3F3A G34W mutations. Recurrence rates were 32% following curettage and 18% after en bloc resection. Denosumab treatment, administered for an average of 14.6 months, facilitated tumor downsizing and new bone formation without major side effects. Histologically, treated tumors showed a depletion of giant cells and increased bone matrix deposition. Conclusions Surgery remains the cornerstone of GCTB treatment, with curettage or resection tailored to tumor characteristics. Denosumab offers a valuable adjunct in high-risk cases, enhancing surgical feasibility and promoting joint preservation. The Campanacci grading system continues to be a crucial tool for prognostication and treatment planning, particularly when complemented by molecular and radiological diagnostics. Future research should focus on integrating advanced imaging and artificial intelligence for personalized GCTB management. Level of evidence: Level 4

Giant cell tumor of bone (GCTB) is a locally aggressive tumor that shows predilection for the metaphysis/epiphysis of long bones, with an incidence of 4–5% of primary bone tumors. GCTB shows two main populations of cells: mononuclear cells and non-neoplastic multi-nucleated giant cells, with or without fibrous background. On the other hand, giant-cell-poor GCTB are rare with only few reports in the literature. These cases offer a diagnostic challenge, given the absence of giant cells and such cases have consistently been shown to harbor the H3F3A gene mutation by sequencing. The H3.3 G34W mutation-specific monoclonal antibody has shown high specificity in the diagnosis of GCTB. Two cases of giant-cell-poor GCTB are presented in this study, in which giant cells were absent or sparse and the diagnosis of GCTB was confirmed by the expression of H3.3 G34W monoclonal antibody in the mononuclear cells by immunohistochemistry. Whether this represents a histologic variant of GCTB or partial involution of GCTB is not yet fully understood; however, an immune response, infectious/inflammatory reaction, and/or anti-tumor cytokine production have been purported to be factors inciting disease regression in GCTB.

Giant cell tumor of the bone (GCTB) is a locally-aggressive, benign tumor that typically affects young adults between 20 and 40 years old. A 15-year-old female presented to a primary care physician with pain in the lateral aspect of the left knee and was referred to our department with a suspected bone tumor owing to radiographic findings of osteolysis of the proximal fibula. Computed tomography indicated osteolysis of the proximal fibula, and the bone cortex was thin and partially irregular. Magnetic resonance imaging indicated a mass in the same area, with hyperintense changes in both T1- and T2-weighted images. No biopsy was performed; however, bone tumor curettage and artificial bone grafting were performed. The final pathological examination indicated osteoclastic, multinucleated giant cells. No malignant findings were observed, and the patient was diagnosed with GCTB. No recurrence was observed one year after surgery. This case highlights the occurrence of GCTB in a young patient at an uncommon location. Oncologic surgeons should consider GCTB as a differential diagnosis when an image shows translucency of the proximal fibula, even if the patient is younger than the usual age of onset.

The receptor-activator of nuclear kappaB ligand (RANKL) signaling pathway plays an important role in the regulation of bone growth and mediates the formation and activation of osteoclasts. Osteoclasts are involved in significant bone resorption and destruction. Denosumab is a fully human monoclonal antibody against RANKL that specifically inhibits osteoclast differentiation and bone resorption. It has been approved for use for multiple myeloma and bone metastases, as well as for giant cell tumor of bone. However, there is no previous report quantitatively, comparing RANKL expression in histologically varied bone tumors. Therefore, we analyzed the mRNA level of various bone tumors and investigated the possibility of these tumors as a new therapeutic target for denosumab. We examined RANKL mRNA expression in 135 clinical specimens of primary and metastatic bone tumors using real-time PCR. The relative quantification of mRNA expression levels was performed via normalization with RPMI8226, a human multiple myeloma cell line that is recognized to express RANKL. Of 135 cases, 64 were also evaluated for RANKL expression by using immunohistochemistry. Among all of the tumors investigated, RANKL expression and the RANKL/osteoprotegerin ratio were highest in giant cell tumor of bone. High RANKL mRNA expression was observed in cases of aneurysmal bone cyst, fibrous dysplasia, osteosarcoma, chondrosarcoma, and enchondroma, as compared to cases of multiple myeloma and bone lesions from metastatic carcinoma. RANKL-positive stromal cells were detected in six cases: five cases of GCTB and one case of fibrous dysplasia. The current study findings indicate that some primary bone tumors present new therapeutic targets for denosumab, particularly those tumors expressing RANKL and those involving bone resorption by osteoclasts.

Background Giant cell tumor of bone is a locally aggressive bone tumor characterized by the proliferation of round-to-oval mononuclear cells and uniformly distributed osteoclast-type giant cells. Giant cell tumor of bone typically arises in long bones, whereas craniofacial involvement is rare. Atypical histological and clinical presentations can complicate diagnosis. This study presents a challenging case of giant cell tumor of bone in the mandible. Case presentation A Japanese man in his 70s presented with a slowly expanding radiolucent lesion in the left mandible, first noted a decade ago, with no subjective symptoms. Cone-beam computed tomography revealed a 27 mm × 12 mm × 23 mm radiolucent lesion with irregular borders and discontinuity of the mandibular canal. Excisional biopsy showed the proliferation of bland spindle cells with small multinucleated cells, which indicated central giant cell granuloma. However, the spindle cells were positive for H3.3G34W, a specific marker of giant cell tumor of bone, which confirmed the diagnosis of giant cell tumor of bone. Conventional histological features of giant cell tumor of bone were absent throughout the observation period. Conclusion Morphological analysis alone is insufficient for diagnosing giant cell tumor of bone, and H3.3G34W immunostaining is valuable in distinguishing it from other giant cell lesions. The possibility of giant cell tumor of bone should not be ruled out in cases involving the jaw, although its occurrence is rare.

AimsDenosumab, a fully human monoclonal antibody directed against RANKL, has recently been introduced in the treatment strategy of giant cell tumour of bone (GCTB). Aim of this study was to investigate the phenotypical modifications induced by denosumab treatment in a series of 15 GCTB.MethodsThe tumours were characterised for histone 3.3 mutations, and studied immunohistochemically for the modifications of RANKL, RANK, SATB2 and RUNX2 expression, as well as of tumour proliferative activity and angiogenesis.ResultsNine of 11 tumours investigated presented a histone 3.3 mutation in H3F3A, and 2 of these for which the analysis was carried out in pretreatment and post-treatment specimens showed the same mutation in both. Denosumab induced the disappearance of osteoclast-like giant cells, leaving residual spindle neoplastic cells arranged in a storiform pattern, with deposition of trabecular collagen matrix and osteoid, which tended to maturation in the peripheral portions of the lesion. RANK and RANKL expression was variable, with no significant variation after treatment. Moreover, we did not observe any significant modification of the expression of the osteoblastic markers SATB2 and RUNX2. Denosumab treatment determined a significant reduction of the proliferative index and of tumour angiogenesis (p=0.001, Wilcoxon rank-sum test).ConclusionsThese results indicate that denosumab induces a partial maturation towards the osteoblastic phenotype of the neoplastic cells of GCTB, with production of fibrous and osteoid matrix, but with minor immunophenotypical changes. Finally, we first report an antiangiogenic activity of denosumab in GCTB, possibly mediated by a RANKL-dependent pathway.

Purpose Denosumab, a novel monoclonal antibody that targets the receptor activator of nuclear factor-κB (RANK) ligand (RANKL), has recently been used to treat patients with giant cell tumor of bone (GCTB). However, few reports have described the clinical results of denosumab therapy for spinal GCTB and evaluated treatment efficacy with respect to the entirety of the resected vertebra after denosumab therapy. Methods We present the case of a 51-year-old man with T12 GCTB that was completely removed by a total spondylectomy following 10 courses of neoadjuvant denosumab therapy. Post-therapy radiological findings indicated epidural tumor reduction in the spinal canal and sclerotic rim formation. However, the affected vertebra collapsed despite denosumab therapy and a massive bridging callus formation was present between the spinal GCTB and adjacent vertebra. Results These morphological changes made the tumor margins unclear and increased the difficulty of dissection of the segmental arteries from the vertebral body and en bloc corpectomy by a posterior-approach. Pathological findings indicated increased woven bone at the peripheral lesion of the resected vertebra and RANKL-positive stromal cells remained around the woven bone. Conclusions These findings support that GCTB stromal cells survived around the newly formed woven bone after long-term denosumab treatment and total surgical resection of such primary spinal lesions as the gold-standard treatment, even following administration of denosumab. Surgeons should note that prolonged adjuvant denosumab therapy may increase the difficulty of performing a posterior-approach total en bloc spondylectomy.

Background A giant cell tumor of bone is a primary benign but locally aggressive neoplasm. Malignant transformation in a histologically typical giant cell tumor of bone, without radiotherapy exposure, is an uncommon event, occurring in less than 1% of giant cell tumors of bone. Although surgery is the standard initial treatment, denosumab, a monoclonal antibody drug that inhibits receptor activator of nuclear factor-κB ligand (RANKL), has shown considerable activity regarding disease and control of symptoms in patients with recurrence, unresectable, and metastatic giant cell tumors of bone. Case Description We report the case of a 20-year-old woman with a recurrent benign, giant cell tumor of bone, who had a bone sarcoma develop while receiving denosumab treatment. Literature Review To our knowledge, there have been no reports of infection or malignancy with low-dose denosumab administration for osteoporosis. However, while there are relatively few reported side effects, the safety of denosumab and adverse events seen with higher doses, as used in treatment of giant cell tumors of bone are not well defined. Clinical Relevance Denosumab has become a valuable adjunct for treatment of recurrent or unresectable giant cell tumor of bone. It is not clear if our patient’s malignant transformation of a giant cell tumor of bone while receiving denosumab treatment was caused by denosumab, but it is important to be aware of the possibility if more cases occur. Future studies should focus on the safety of high-dose denosumab administration in patients with a benign unresectable giant cell tumor of bone.

PurposeThis study aimed to investigate whether short course of neoadjuvant denosumab treatment for spinal GCTB could (1) Induce radiological and histological response? (2) Facilitate en bloc resection? (3) Achieve satisfactory oncological and functional outcomes?MethodsThe clinical information of ten consecutive patients between 2018 and 2022 with spinal GCTB treated with short course of neoadjuvant denosumab (≤ 5 doses) and en bloc spondylectomy was retrospectively reviewed. The radiological and histological response, operative data, oncological and functional outcomes were analyzed.ResultsThe mean doses of neoadjuvant denosumab were 4.2 (range 3–5 doses). After neoadjuvant denosumab, there were 9 cases showing new ossification and 5 cases with reappearance of cortical integrity. The values of Hounsfield units (HU) of the soft tissue component were increased by > 50% in 7 cases. The signal intensity (SI) ratios of tumor/muscle in T2WI of plain MRI were decreased by > 10% in 60% of the cases. Shrinkage of soft tissue mass by > 10% was observed in 4 cases. The mean duration of operation was 575 ± 174 min, and the mean estimated blood loss (EBL) was 2790 ± 1934 ml. No obvious adhesion to dura mater or major vessels was encounter intraoperatively. There is no tumor collapse or breakage during surgery. Multinucleated giant cells were decreased in 6 cases (60%) with the remaining 4 cases showing absence of multinucleated giant cells. Mononuclear stromal cells existed in most of the cases (8 cases, 80%). New bone formation was noticed in 8 cases (80%). No patient had a worsening of neurologic function after surgery. No tumor recurrence was noticed within the mean follow-up of 24 ± 20 months.ConclusionShort-term neoadjuvant denosumab could yield radiological and histological responses and might facilitate en bloc spondylectomy by hardening the tumor and causing less adhesion to segmental vessels, major vessels and nerve roots, which was beneficial to achieve the optimal oncological and functional outcomes.