Giant cell tumor of bone is a benign albeit aggressive tumor commonly affecting the bones of the knee. Patients with these tumors present with pain, swelling, and inability to bear weight on the involved extremity. These destructive tumors typically arise in the metaphyseal region of the long bones in individuals in the second, third, and fourth generations of life. Histologically, the multinucleated giant cells are the hallmark of the lesion, easily recognized on histological review, which recently have become therapeutic targets for medical management of the disease. For decades, surgical management has been the primary treatment for giant cell tumor of the bone. Some tumors can be treated with excision and filling of the osseous void with bone cement or allograft. This is an effective treatment option with a low to moderate risk of local recurrence while preserving limb function. For more destructive tumors, wide excision and reconstruction with prosthetic, structural allograft or combined allograft prosthetic components are utilized. Advances in medical management of the disease have also demonstrated promise as an effective treatment; however, its use has usually been limited to the treatment of metastatic disease, recurrent disease or when advanced local disease would require surgical treatment felt to be overly morbid.

Giant Cell Tumor of Bone: Review of Current Literature, Evaluation, and Treatment Options.

Purpose of reviewGiant cell tumor of bone (GCTB) is an uncommon benign primary bone tumor, consisting of receptor activator of nuclear factor kappa-B (RANK) expressing reactive osteoclast-like giant cells and neoplastic spindle-shaped cells. Denosumab was approved by FDA in 2013 and by EMA in 2014 t

Challenges of denosumab in giant cell tumor of bone, and other giant cell-rich tumors of bone

Recent clinical studies have suggested that denosumab is associated with beneficial tumour response, surgical down-staging, and reduced surgical morbidity in patients with giant cell tumour of bone. However, these studies reported results of patients still on denosumab treatment, or patients after denosumab treatment but with a short follow-up. Other studies reported that the new osseous tumour matrix and thickened cortical bone that develop with denosumab treatment does not allow the surgeon to delineate the true extent of the tumour, and probably increases the risk for local recurrence. A study showed that cell proliferation is only diminished by denosumab; the cells continue to proliferate in vitro, albeit at a slower rate. More importantly, nine cases of malignant transformation of GCT during denosumab therapy without previous radiation exposure have been reported; inhibition of RANKL may increase the risk of new malignancies due to immunosuppression. With these concerns in mind, this article is an attempt to put essential information in one place, creating a comprehensive review that the curious reader would find interesting and informative.

How safe and effective is denosumab for bone giant cell tumour

Aims Denosumab, a human monoclonal antibody directed against the receptor activator of nuclear factor-κB ligand (RANKL), is a therapeutic agent for giant cell tumour of bone (GCTB). Although some studies have reported that denosumab shrinks tumours and induces bone formation, the actual effects of RANKL suppression on GCTB remain unclear. A mutation in the H3 histone family member 3A gene (H3F3A) was recently identified as a genetic signature for GCTB. The aim of this study was to investigate the histopathological features and H3F3A mutation status of GCTBs treated with denosumab. Methods and results Nine biopsy-diagnosed patients with GCTB, who underwent curettage after neoadjuvant denosumab therapy, were reviewed. Immunohistochemistry for NFATc1 (an osteoclast marker), RUNX2 (an osteoblast marker) and histone H3.3 G34W (G34W, a GCTB marker) was performed; furthermore, H3F3A mutation status was examined with direct sequencing. Before therapy, GCTBs comprised NFATc1+ and RUNX2+ cells. All cases were G34W+ and contained H3F3A mutations. After therapy, the osteoclast-like giant cells disappeared. Areas of slender spindle cell proliferation and reticular woven bone that were NFATc1- and RUNX2+ replaced the lesions in various proportions. However, all post-therapy lesions still contained many G34W+ cells and harboured H3F3A mutations. Immunofluorescence double staining revealed that RUNX2+ mononuclear cells coexpressed G34W in pre-therapy and post-therapy lesions. Two patients experienced radiologically detected local recurrence within 2 years. Conclusions Denosumab therapy effectively decreases the number of osteoclastic cells in GCTBs. However, the neoplastic cells with H3F3A mutation survive denosumab treatment and undergo dramatic histological changes in response to this agent.

Giant cell tumours of bone treated with denosumab: histological, immunohistochemical and H3F3A mutation analyses.

BACKGROUND Although giant cell tumors (GCTs) are benign, their aggressiveness and tendency to recur locally challenge the orthopaedic surgeon's ability to perform joint-preserving intralesional surgery with an acceptably low risk of local recurrence. Denosumab has emerged as a possible medical treatment of GCT because it seems to halt the progression of GCT, alleviate pain, and increase perilesional bone formation, but its exact role has been questioned, and specifically its efficacy and associated complications are not well characterized. QUESTIONS/PURPOSES (1) Does denosumab reduce the risk of recurrence after resection or intralesional surgery? (2) What are the complications associated with the use of denosumab? METHODS Fifty-four patients with 30 primary and 25 recurrent tumors between November 2013 and July 2016 were treated with denosumab after a confirmed histopathologic diagnosis of GCT. Another 17 patients in the same period were treated without denosumab. During the study period, we encouraged the use of denosumab in all patients except those who refused, could not afford it, or where it was contraindicated (eg, in pregnancy). In all patients undergoing intralesional surgery, we arbitrarily planned six doses before surgery. Variations in total doses before surgery were dependent on patient-related factors; in some, we gave less doses because patients expressed the inability to afford any more doses, whereas in some patients, extra doses were added when the patient wished to delay surgery as well as the because of surgeon judgment wherein in some patients, we stopped before six doses when we thought adequate bone had formed for intralesional curettage. The mean number of doses was 6.8 per patient (median, 6; range, 3-17) preoperatively. The minimum followup was 12 months (median, 27 months; range, 12-42 months). Every patient showed improvement clinically in terms of pain and halting of tumor progression within three to four doses. This was seen radiologically as a sharply defined soft tissue mass as well as hazy ossification within the tumor. For a case-matched comparison study, we identified controls as 34 patients undergoing curettage from the retrospective analysis of 68 patients curetted without denosumab between February 2010 and July 2016 matched to 25 denosumab-treated patients in terms of site, size, Campanacci grade, and recurrent versus primary status, and with a minimum 2 years followup for the control group. Fisher's exact test was used for statistical study. Patients undergoing resection were planned for surgery after three doses of denosumab to allow the tumor to solidify and potentially decrease tumor spillage at the time of surgery. The resections could not be case-matched for comparison owing to the smaller numbers. RESULTS We observed 14 recurrences out of the 37 curetted tumors (38%). In the case-matched analysis, 11 of 25 patients in the denosumab-treated curettage group had recurrences (44%) compared with seven of 34 (21%) in the nondenosumab-treated control group. The risk of denosumab-treated patients experiencing local recurrence as compared with the nondenosumab-treated patients was nonsignificant with a two-tailed p value of 0.085 (significance at p < 0.05) as derived from Fisher's exact test (odds ratio, 3.03; 95% confidence interval, 0.96-9.54). There was no recurrence in the resection group. Because we do not have a control group for resection, we are unable to comment on the importance of this finding. One major complication that we observed was a recurrence with malignant transformation in a patient with a proximal humeral GCT. We did not observe any other complications related to the denosumab therapy. CONCLUSIONS Although we could not demonstrate a higher risk of local recurrence with preoperative denosumab for intralesional surgery in the dose and frequency we administered, we advise caution in its routine use for intralesional procedures because it may be important to curette up to margins on pretreatment imaging owing to the potential residual tumor within the denosumab-mediated thick bony shell, which may result in local recurrence. We believe that denosumab treatment before resection of a large tumor aids resection without tumor spillage, particularly where important structures like the neurovascular bundle are dissected away from the tumor margin, although we cannot confirm that it helps lower the incidence of recurrence. We are concerned regarding the malignancy-causing potential from our observation in one patient as well as reports of this by others and recommend judicious use of this drug in patients with GCT. LEVEL OF EVIDENCE Level III, therapeutic study.

Does Denosumab Change the Giant Cell Tumor Treatment Strategy? Lessons Learned From Early Experience

Giant cell tumor (GCT) of bone is a generally benign, but often locally aggressive, neoplasm of bone, with a propensity for recurrence. Sarcomatous transformation is rare and typically occurs with a history of recurrences and radiation treatment. Denosumab, an inhibitor of the RANK ligand involved in bone resorption in GCT, is increasingly used in treatment of recurrent or unresectable giant cell tumor of bone. We report two cases of sarcomatous transformation of GCT to osteosarcoma in patients receiving denosumab. One was a 59-year-old male with a 12-year history of GCT and multiple recurrences taking denosumab for 2.5 years. The second case was in a 56-year-old male with a seven-year history of GCT taking denosumab for six months. Review of the literature shows one case report of malignant transformation of GCT in a patient being treated with denosumab. As the use of denosumab for treatment of GCT will likely increase, larger, controlled studies are needed to ascertain whether denosumab may play a role in malignant transformation of giant cell tumor of bone.

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Two Cases of Sarcoma Arising in Giant Cell Tumor of Bone Treated with Denosumab

Background Although the rate of non-fatal gunshot wounds (GSW) has increased, few studies have compared the effectiveness of operative and nonoperative treatment with specific focus on infection. We compared the risk of septic arthritis in patients with traumatic arthrotomies caused by GSW treated operatively with irrigation and debridement versus nonoperatively with antibiotics and wound care. Methods From 2009 to 2016, 46 patients at our institution sustained traumatic arthrotomies from low-velocity GSW with at least 90-day follow-up. Medical records were reviewed for demographic information, imaging, type and duration of antibiotics, details of operative and nonoperative interventions, and evidence of infection at follow-up visits. We measured the rate of septic arthritis using a 2-tailed t test. Results The knee was the most commonly affected joint (34 patients; 73.9%). Eight patients (17.4%) were treated nonoperatively and 38 (82.6%) were treated operatively. In the nonoperative group, one patient (12.5%) developed a superficial wound infection that resolved with oral antibiotics. In the operative group, one patient (2.6%) developed a superficial wound infection requiring operative irrigation and debridement. There was no statistically significant difference in risk of infection between the two groups (P = 0.32). No patient developed septic arthritis. Conclusions In select patients, nonoperative treatment with wound care and antibiotics may be sufficient for preventing infection after GSW-related traumatic arthrotomies. Findings of randomized studies and treatment algorithms are needed to further evaluate this relatively common injury.Level of Evidence: IV.

Operative Versus Nonoperative Management Of Traumatic Arthrotomies from Civilian Gunshot Wounds.

Topical povidone-iodine, chlorhexidine, bacitracin, and vancomycin are commonly used antiseptic and antimicrobial agents to reduce risk and treat surgical site infections in numerous orthopedic procedures. Chondrocytes potentially may be exposed to these agents during operative procedures. The impact of these topical agents on chondrocyte viability is unclear. The goal of this study is to determine human chondrocyte viability ex vivo after exposure to commonly used concentrations of these topical antiseptic and antimicrobial agents. Human osteochondral plugs were harvested from the knee joint of a human decedent within 36 hours of death. Individual human osteochondral plugs were exposed to normal saline as a control; a range of concentrations of povidone-iodine (0.25%, 0.5%, and 1%), chlorhexidine (0.01% and 0.5%), and bacitracin (10,000 units/L, 50,000 units/L, and 100,000 units/L) for 1-minute lavage; or a 48-hour soak in vancomycin (0.16 mg/mL, 0.4 mg/mL, and 1.0 mg/mL) with nutrient media. Chondrocyte viability was evaluated with a live/dead viability assay at 0, 2, 4, and 6 days after exposure to bacitracin at 0, 3, and 6 days). Control subjects showed greater than 70% viability at all time points. Povidone-iodine, 0.5% chlorhexidine, and vancomycin showed significant cytotoxicity, with viability dropping to less than 40% by day 6. Chondrocytes exposed to 0.01% chlorhexidine maintained viability. Chondrocytes exposed to bacitracin showed viability until day 3, when there was a large drop in viability. Commonly used topical concentrations of povidone-iodine, vancomycin, and bacitracin are toxic to human chondrocytes ex vivo. A low concentration of chlorhexidine appears safe. Caution should be used when articular cartilage may be exposed to these agents during surgery. [Orthopedics. 20XX;XX(X):xx-xx.].

Erika L. Garbrecht

Papers

Two Cases of Sarcoma Arising in Giant Cell Tumor of Bone Treated with Denosumab

Operative Versus Nonoperative Management Of Traumatic Arthrotomies from Civilian Gunshot Wounds.

Ex Vivo Toxicity of Commonly Used Topical Antiseptics and Antibiotics on Human Chondrocytes.