**3. Treatment overview**

shows that spindle cells and cells in and around immature bone in denosumabtreated GCTBs are H3.3 p.G34W-positive by IHC, with H3F3A mutations consistently detected in corresponding samples [56, 58, 60, 61], which may predict

Although rare, malignant GCTB may occur, and studies suggest that p.G34W mutation is preserved [55]. One report, however, showed loss of one *H3F3A* allele (probably the mutant allele) in GCTB malignant component, leading to negative p.

p63, a member of the p53 family of transcription factors, has also been studied as biomarker in GCTB diagnosis. p63 immunostaining has been used in diagnosis of head and neck squamous cell carcinoma, prostate adenocarcinoma (negative for p63 in opposition to p63-positive benign prostatic tissue) [63], and poorly differentiated squamous cell carcinoma [64]. p63 has also been shown to be highly expressed in GCTB mononuclear neoplastic cells [65–67], but its usefulness is still to be determined. A meta-analysis of eight different studies including 335 GCTB patients showed that p63 is a helpful marker for GCTB diagnosis in critically ill patients, although it cannot be recommended as a single definitive diagnostic

*Flowchart of GCTB treatment. Adapted from NCCN guidelines – Bone cancer [73]. CT, computorized*

*tomography; MRI, magnetic resonance imaging; RT, radiation therapy; SC, subcutaneous.*

relapse risk [55].

*Recent Advances in Bone Tumours and Osteoarthritis*

G34W IHC [62].

marker [68].

**Figure 3.**

**60**

Treatment options for localized GCTB include *en bloc* resection or curettage with or without local adjuvants, like phenol, liquid nitrogen, or polymethylmethacrylate [70]. Radiation therapy (RT) can also be used as an alternative to surgery for local control, with 5-year local control rates of 80% [71]. However, RT is associated with risk of malignant transformation into high-grade sarcoma, making surgery the preferred option when possible. Contrarily to palliative care in irresectable or distant disease, systemic neoadjuvant or adjuvant therapy with the RANKL-binding fully human monoclonal antibody denosumab is still not established [70, 72]. A treatment algorithm is depicted in **Figure 3**.
