The Activation of PDGFRβ on Mononuclear Stromal/Tumor Cells in Giant Cell Tumor of Bone After Denosumab Treatment. An Immunohistochemical Study of Five Cases

Abstract

Due to the relatively high recurrence rate and the destructive nature of the tumor, the treatment of giant cell tumor is still a challenge. Denosumab appeared to be a promising candidate as a therapeutic drug. However, several studies have reported that tumors can recur during/after treatment with denosumab. Based on activated receptor tyrosine kinase signaling pattern of the stromal/tumor cells, a combination treatment with denosumab and sunitinib has recently been proposed to inhibit recurrences. This prompted us to investigate the PDGFRβ expression of five denosumab treated cases using both primary and recurrent tumors during and after denosumab treatment. In addition, to recognise morphological changes, immunohistochemical analysis of H3F3A and PDGFRβ was also performed. As an effect of denosumab treatment, the permanent absence of giant cells associated with severe to mild fibrosis was the most consistent morphological change, but H3F3A positive stromal/tumor cells were observed in all cases. Furthermore, an increased immunopositivity of PDGFRβ in stromal/tumor cells was evident in all recurrent cases during denosumab treatment. Upon tumor recurrence (after the discontinuation of denosumab treatment) the intensity of PDGFRβ immunostaining in stromal/tumor cells was restored/decreased. Our results confirm (for the first time) the activation of PDGFRβ on mononuclear stromal/tumor cells at protein level as an effect of denosumab treatment, which has so far only been demonstrated by phosphoprotein array analysis (protein lysates). The decreased PDGFRβ activity after the discontinuation of denosumab treatmeant and the increased PDGFRβ activity during denosumab treatment underlines the need for denosumab and sunitinib combination therapy.

Current indications for denosumab in benign bone tumours

“…Recently, our workgroup ( 1 ) published results about the activation of the tyrosine kinase receptor (PDGFRß) on mononuclear tumour cells in GCTB during denosumab treatment. According to the retrospective immunohistochemical investigation of our five patients with local recurrent GCTB we found that during denosumab treatment the giant cells were completely absent with severe or mild fibrosis, but H3F3A-positive tumour cells could be observed continuously in all cases.…”

“…As a consequence, osteoclasts disappear from the tumour tissue, and they are mostly replaced by loose connective tissue and newly formed bone. H3F3A-positive stromal cells can, however, be detected in the remaining tumour tissue underlining the ineffectiveness of denosumab on the tumourous stromal cells ( 1 ).…”