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