In group A, SAE was used as preoperative treatment for SGCT in this study. It could relieve pain by ossification in tumor. However, no obvious evidence indicated it could decrease the tumor size [12, 20]. Denosumab could inhibit RANK–RANKL interactions and prevent GCTB-induced bone destruction. Recently, it has played a significant role in treating unsalvageable GCTB . The tumor’s metabolic activity, blood supply, and volume was reported to decrease after preoperative use of denosumab . A nonrandomized controlled study of SGCT with preoperative denosumab treatment indicated that intraoperative blood loss was significantly reduced .
In current study, the operation time and blood loss of Group B (curettage + one arterial embolization + denosumab) were significantly less than those of Group A. The effects of denosumab were consistent with previous reports [21, 23]. The preoperative use of denosumab could reduce tumor’s blood supply , which was demonstrated by angiography in current study. It was speculated that denosumab had inhibitory effect on endothelial growth factor, thus decreased endothelial proliferation. The decreased blood supply was helpful to acquire clearly visible operation field, which facilitated the meticulous curettage. However, the span of preoperative denosumab treatment is of great importance. In present study, we followed the protocol reported by Chawla et al . The patients underwent surgeries within the third week after denosumab (120 mg) administration on day 1, 8, and 15 before operation. The literature indicated that overlong pretreatment could increase the bony septa and form the dense fibrous tissue adhered to sacral nerves. It was difficult to separate the nerves from tumor .
Very few studies have been published regarding histopathologic changes in post-denosumab treated tumor specimens. In present study, the pre-operative biopsy showed multinucleated giant cells with uniform vesicular nucleus and mononuclear cells with spindle shape[27, 28]. The post-operative histology of specimens showed the giant cell numbers decreased significantly and cells nearly disappeared in 9 cases. Meanwhile, the osteoblast-like cells appeared and produced a large amount of fibro-osseous tissue (Fig. 4G, 4H). Rekhi et al  reported the similar results. Twenty-seven post denosumab-treated tumors were analyzed. They observed complete absence of giant cells in 15 cases and marked reduction (more than 90%) of giant cells in 9 cases. Compared with our results, their specimens showed more reduction or elimination of RANK-positive tumor giant cells. The reason maybe that most patients (16) (59.2%) received 6 doses of denosumab in their study. Only 3 doses were used in our study considering the feasibility of performing curettage to avoid dense fibrous adhesion.
The reported recurrence, metastasis, and complications of SGCT patients were summarized in Table 2. Local recurrence was reported to occur in 10–66.7% of patients. The effects of SAE and radiotherapy on recurrence control are controversial. Ruggieri et al  reported 31 SGCT patients and three (10%) had local recurrence within 34 months from initial treatment. Survival to local recurrence with and without radiation was 91% and 89%, with and without embolization was 91% and 86% respectively. Adjuvants had no influence on local recurrence. Domovitov et al.  reported 24 SGCT patients and local recurrence rate was 30%. Radiation and preoperative embolization were associated with prolonged disease-free survival. There was no local recurrence among the 11 patients who were treated with both modalities. Regarding to the effect of denosumab, Yang et al. reported that six patients received preoperative denosumab treatment for 5.2 months. After 12 months of follow-up, the recurrence rate was relatively high (66.7%). The authors thought the newly formed bone induced by denosumab raised a new surgical challenge by not allowing surgeon to delineate the true extent of tumor. The tumor cells might hide within the new osseous matrix. In present study, the recurrence in denosumab treatment group was 2 in 18 cases (11.1%), which was much lower than that of group A. The results were similar to the data reported by Chen et al. . This rate was lower than most rates previously reported by using other adjuvant therapies [31–33]. Recently, Lim et al.  evaluated therapeutic benefits of denosumab on nerve-sparing surgery in SGCT. They reported the similar local recurrence rate (3/17, 17.6%) in neo- and adjuvant denosumab group. In addition to correlating their results, this study indicated neo-adjuvant denosumab treatment could decrease the tumor’s blood supply and thereby reduce the number of arterial embolization. The low recurrence rate in current study could be explained by aggressive curettage performed in clearly visible operation field due to the decrement of tumor’s blood supply after denosumab treatment.
At the present time, it is important to confirm whether the treatment with denosumab can be safely maintained in the long term. Chawla et al  investigated 532 patients with the median follow-up of 58.1 months in a multicenter, open-label, phase 2 study. Patients received 120 mg subcutaneous denosumab once every 4 weeks during the treatment phase. The most common adverse events were hypophosphataemia (24, 5%) and ONJ (17, 3%). However, no case of hypophosphataemia and ONJ was observed in our study. The reasons might lie in: 1) Patients with a history or current evidence of osteonecrosis or osteomyelitis of the jaw were excluded; 2) The included patients were told to avoid oral operation during the period of denosumab treatment; 3) Patients took daily supplements of calcium (> 500 mg) and vitamin D (> 400 IU) to prevent hypocalcemia. Another severe complication is sarcomatous transformation. The first case with sarcomatous transformation after denosumab treatment was reported by Aponte-Tinao et al in 2015. Thereafter, other studies also reported such complication with the frequency ranging from 1–2% [16, 26, 36]. Although there is no clear association between malignancy and denosumab treatment, these findings suggest radiological and pathological examinations should monitor the sarcomatous change. There was no patient with sarcomatous transformation in our study, which might be attributed to the small sample size.
The authors acknowledge several limitations in present study. Firstly, this is the retrospective study, which might induce information bias despite being one of the large series on the denosumab treatment SGCT; Secondly, perhaps given the relatively small sample size, we found no significant difference in recurrence rate between group A (surgery + SAE + radiotherapy) and B (surgery + onearterial embolization + denosumab), although the latter was much lower. Larger studies might determine that denosumab has statistically significant influence on recurrence; Thirdly, the confounding variables such as the volume, size, location, and aggressiveness of the tumors could not be controlled among groups, these factors might weaken the accuracy of the statistical analysis to some extent.