Denosumab-treated Giant Cell Tumors of Bone: A Clinicopathologic Analysis of 35 Cases From the French Group of Bone Pathology

Abstract

Denosumab, an antibody directed against receptor activator of nuclear factor-κB ligand (RANKL), has recently been introduced in the treatment strategy of giant cell tumor of bone. In this study, we assessed the tumor changes induced by denosumab in a national multicentric series of 35 cases (French Bone Pathology Group network—ResOs). Tissue specimens collected before and after denosumab treatment were investigated for RANKL, H3.3 G34W, p63, and Ki-67 expression, and for H3F3A mutation. These parameters were put in correspondance with clinical and radiologic presentation to identify prognostic factors, and more specifically, predictive markers of an optimal histologic response to denosumab, identified as a ≥50% loss in giant cells with fibrosis and ossification. The main changes in posttreatment specimens showed an induction of ossification (P=2.10−5), an increased fibrosis (P=3.10−5), and a major decrease in giant cells (P=6.10−11). No significant change in mononuclear tumor cell density and in patterns of expression of RANKL (P=0.061) and H3.3 G34W was observed (P=0.061). An optimal histologic response to denosumab treatment was associated with an enhanced progression-free survival (P=0.010 in univariate analyses; P=0.040 in multivariate analyses). The initial number of giant cells was predictive of the histologic response to treatment (P=0.016). In summary, denosumab treatment induced radical changes in the tumor. The histologic response, despite the absence of objective regression of the mononuclear cells, was associated with an enhanced progression-free survival. Greater numbers of giant cells represented the only predictive indication of an optimal histologic response to denosumab treatment.

Giant Cell-Rich Tumors of Bone

“…The multinucleated giant cells disappear, and the lesional mononuclear cells decrease and partly transform into osteoblasts forming varying amounts of immature woven bone trabeculae. 3,4 This observation is in line with gene expression profiles of the mononuclear component of GCT that resemble those of cells with early osteoblastic differentiation. 5 In some cases, reactive atypia can be striking and mimic malignant transformation.…”

Late Local Recurrence of Bone Giant Cell Tumors Associated with an Increased Risk for Malignant Transformation

“…The efficacy and safety of denosumab for GCTB treatment have been reported, and the U.S. Food and Drug Administration approved the use of denosumab in 2013 [ 14 ]. However, 12 cases of malignant transformation of GCTB during and after denosumab treatment have been reported [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ], suggesting that denosumab treatment is associated with malignant transformation [ 33 ]. According to recent systematic reviews, the cumulative incidence of secondary malignant GCTB without a history of radiotherapy or denosumab treatment was 0.6% [ 8 ].…”

“…Agarwal et al [ 16 ] have observed that malignant transformation occurred in 1 of 25 patients (4%) after a median follow-up of 27 months after denosumab was administered for 8 months postoperatively. Treffel et al [ 23 ] have revealed that, among 35 patients who presented with GCTB and received denosumab treatment, malignant transformation occurred in one patient (2.9%), 18 months postoperatively. Recently, Perrin et al [ 21 ] have reported that malignant transformation occurred in one of 25 patients (4%) with GCTB at a median follow-up of 57 months after denosumab administration, 55 months postoperatively.…”

“…Inclusion criteria included patients with GCTB of the extremities who had a postoperative follow-up period of 6 months or longer. Exclusion criteria included patients with primary malignant GCTB and missing data, patients with a history of radiotherapy owing to the possible relationship between radiotherapy and malignant transformation [ 8 ], and patients who received denosumab for GCTBs, owing to the possible association between denosumab administration and malignant transformation [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. We retrieved the following data from the patients’ medical records: age, sex, site, Campanacci stage of GCTB [ 4 ], previous surgery (curettage or en-bloc resection in another hospital), surgery type, local recurrence, lung metastasis (synchronous or metachronous), malignant transformation, and follow-up period.…”

Giant cell tumor of bone – Analysis of 213 cases involving extra‐craniofacial bones

“…Denosumab, a RANK ligand inhibitor, is frequently used now in the treatment of GCTB, especially for unresectable tumors. 27 , 28 Favorable outcome following its use have been reported 46 , 47 but some recent studies reported otherwise. 48 , 49 By multivariate analysis, our study shows that denosumab therapy increases the risk for local recurrence as a significant trend level ( P = 0.053).…”