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The Bone & Joint Journal
Vol. 105-B, Issue 5 | Pages 559 - 567
1 May 2023
Aoude A Nikomarov D Perera JR Ibe IK Griffin AM Tsoi KM Ferguson PC Wunder JS

Aims. Giant cell tumour of bone (GCTB) is a locally aggressive lesion that is difficult to treat as salvaging the joint can be associated with a high rate of local recurrence (LR). We evaluated the risk factors for tumour relapse after treatment of a GCTB of the limbs. Methods. A total of 354 consecutive patients with a GCTB underwent joint salvage by curettage and reconstruction with bone graft and/or cement or en bloc resection. Patient, tumour, and treatment factors were analyzed for their impact on LR. Patients treated with denosumab were excluded. Results. There were 53 LRs (15%) at a mean 30.5 months (5 to 116). LR was higher after curettage (18.4%) than after resection (4.6%; p = 0.008). Neither pathological fracture (p = 0.240), Campanacci grade (p = 0.734), soft-tissue extension (p = 0.297), or tumour size (p = 0.872) affected the risk of recurrence. Joint salvage was possible in 74% of patients overall (262/354), and 98% after curettage alone (262/267). Of 49 patients with LR after curettage, 44 (90%) underwent repeated curettage and joint salvage. For patients treated by curettage, only age less than 30 years (p = 0.042) and location in the distal radius (p = 0.043) predicted higher LR. The rate of LR did not differ whether cement or bone graft was used (p = 0.753), but may have been reduced by the use of hydrogen peroxide (p = 0.069). Complications occurred in 15.3% of cases (54/354) and did not differ by treatment. Conclusion. Most patients with a GCTB can undergo successful joint salvage by aggressive curettage, even in the presence of a soft-tissue mass, pathological fracture, or a large lesion, with an 18.4% risk of local recurrence. However, 90% of local relapses after curettage can be treated by repeat joint salvage. Maximizing joint salvage is important to optimize long-term function since most patients with a GCTB are young adults. Younger patients and those with distal radius tumours treated with joint-sparing procedures have a higher rate of local relapse and may require more aggressive treatment and closer follow-up. Cite this article: Bone Joint J 2023;105-B(5):559–567


Bone & Joint Research
Vol. 13, Issue 2 | Pages 83 - 90
19 Feb 2024
Amri R Chelly A Ayedi M Rebaii MA Aifa S Masmoudi S Keskes H

Aims. The present study investigated receptor activator of nuclear factor kappa-Β ligand (RANKL), osteoprotegerin (OPG), and Runt-related transcription factor 2 (RUNX2) gene expressions in giant cell tumour of bone (GCTB) patients in relationship with tumour recurrence. We also aimed to investigate the influence of CpG methylation on the transcriptional levels of RANKL and OPG. Methods. A total of 32 GCTB tissue samples were analyzed, and the expression of RANKL, OPG, and RUNX2 was evaluated by quantitative polymerase chain reaction (qPCR). The methylation status of RANKL and OPG was also evaluated by quantitative methylation-specific polymerase chain reaction (qMSP). Results. We found that RANKL and RUNX2 gene expression was upregulated more in recurrent than in non-recurrent GCTB tissues, while OPG gene expression was downregulated more in recurrent than in non-recurrent GCTB tissues. Additionally, we proved that changes in DNA methylation contribute to upregulating the expression of RANKL and downregulating the expression of OPG, which are critical for bone homeostasis and GCTB development. Conclusion. Our results suggest that the overexpression of RANKL/RUNX2 and the lower expression of OPG are associated with recurrence in GCTB patients. Cite this article: Bone Joint Res 2024;13(2):84–91


The Bone & Joint Journal
Vol. 103-B, Issue 1 | Pages 184 - 191
1 Jan 2021
Perrin DL Visgauss JD Wilson DA Griffin AM Abdul Razak AR Ferguson PC Wunder JS

Aims. Local recurrence remains a challenging and common problem following curettage and joint-sparing surgery for giant cell tumour of bone (GCTB). We previously reported a 15% local recurrence rate at a median follow-up of 30 months in 20 patients with high-risk GCTB treated with neoadjuvant Denosumab. The aim of this study was to determine if this initial favourable outcome following the use of Denosumab was maintained with longer follow-up. Methods. Patients with GCTB of the limb considered high-risk for unsuccessful joint salvage, due to minimal periarticular and subchondral bone, large soft tissue mass, or pathological fracture, were treated with Denosumab followed by extended intralesional curettage with the goal of preserving the joint surface. Patients were followed for local recurrence, metastasis, and secondary sarcoma. Results. A total of 25 patients with a mean age of 33.8 years (18 to 67) with high-risk GCTB received median six cycles of Denosumab before surgery. Tumours occurred most commonly around the knee (17/25, 68%). The median follow-up was 57 months (interquartile range (IQR) 13 to 88). The joint was salvaged in 23 patients (92%). Two required knee arthroplasty due to intra-articular fracture and arthritis. Local recurrence developed in 11 patients (44%) at a mean of 32.5 months (3 to 75) following surgery, of whom four underwent repeat curettage and joint salvage. One patient developed secondary osteosarcoma and another benign GCT lung metastases. Conclusion. The use of Denosumab for joint salvage was associated with a higher than expected rate of local recurrence at 44%. Neoadjuvant Denosumab for joint-sparing procedures should be considered with caution in light of these results. Cite this article: Bone Joint J 2021;103-B(1):184–191


Bone & Joint Open
Vol. 3, Issue 7 | Pages 515 - 528
1 Jul 2022
van der Heijden L Bindt S Scorianz M Ng C Gibbons MCLH van de Sande MAJ Campanacci DA

Aims. Giant cell tumour of bone (GCTB) treatment changed since the introduction of denosumab from purely surgical towards a multidisciplinary approach, with recent concerns of higher recurrence rates after denosumab. We evaluated oncological, surgical, and functional outcomes for distal radius GCTB, with a critically appraised systematic literature review. Methods. We included 76 patients with distal radius GCTB in three sarcoma centres (1990 to 2019). Median follow-up was 8.8 years (2 to 23). Seven patients underwent curettage, 38 curettage with adjuvants, and 31 resection; 20 had denosumab. Results. Recurrence rate was 71% (5/7) after curettage, 32% (12/38) after curettage with adjuvants, and 6% (2/31) after resection. Median time to recurrence was 17 months (4 to 77). Recurrences were treated with curettage with adjuvants (11), resection (six), or curettage (two). Overall, 84% (38/45) was cured after one to thee intralesional procedures. Seven patients had 12 months neoadjuvant denosumab (5 to 15) and sixmonths adjuvant denosumab; two recurred (29%). Twelve patients had six months neoadjuvant denosumab (4 to 10); five recurred (42%). Two had pulmonary metastases (2.6%), both stable after denosumab. Complication rate was 18% (14/76, with 11 requiring surgery). At follow-up, median MusculoSkeletal Tumour Society score was 28 (18 to 30), median Short Form-36 Health Survey was 86 (41 to 95), and median Disability of Arm, Shoulder, and Hand was 7.8 (0 to 58). Conclusion. Distal radius GCTB treatment might deviate from general GCTB treatment because of complexity of wrist anatomy and function. Novel insights on surgical treatment are presented in this multicentre study and systematic review. Intralesional surgery resulted in high recurrence-rate for distal radius GCTB, also with additional denosumab. The large majority of patients however, were cured after repeated curettage. Cite this article: Bone Jt Open 2022;3(7):515–528


Orthopaedic Proceedings
Vol. 93-B, Issue SUPP_I | Pages 76 - 76
1 Jan 2011
Gibbons CLMH Jones F Taylor R Knowles H Hogendoorn P Wass JAH Balke M Picci P Gebert C Athanasou NA
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Introduction: Giant cell tumour of bone (GCTB) is an expansile osteolytic tumour of bone which contains numerous osteoclast-like giant cells. GCTB is a locally aggressive tumour which can cause extensive bone destruction that can be difficult to control surgically, up to 35% of cases recurring after simple curettage. Bisphosphonates are anti-resorptive agents that have proved effective in the treatment of a number of osteolytic conditions. Methods: This study reports results from four European centres where bisphosphonates are being used to treat problematic GCTBs. Details of treatment with bisphosphonates of 25 cases of primary, recurrent and metastatic GCTBs was assessed clinically and radiologically. Results: Most primary/recurrent tumours did not exhibit progressive enlargement and, in some cases, both primary and metastatic GCTBs showed a degree of radiological improvement following treatment. Some patients also noted relief of pain following treatment. In a few cases, no apparent treatment effect was noted and there was disease progression. Several inoperable large spinal/pelvic GCTBs remained stable in size following treatment. Discussion: Our findings provide preliminary evidence for the use of bisphosphonates to inhibit the progressive osteolysis associated with GCTB. These agents had a beneficial clinical and/or radiological effect in most cases. This study reports results from four European centres and highlights the fact that these centres are all employing different clinical indications and different regimes of bisphosphonate treatment. Bisphosphonates have significant side effects and indications for treatment and standardisation of drug type and dosage regimes (and measurement of agreed outcome measures to determine treatment efficacy) should be established for the use of these agents to control GCTB tumour growth and osteolysis


The Journal of Bone & Joint Surgery British Volume
Vol. 86-B, Issue 2 | Pages 212 - 216
1 Mar 2004
Zhen W Yaotian H Songjian L Ge L Qingliang W

Giant-cell tumour of bone (GCT) is a locally benign aggressive tumour. The use of adjuvant agents, such as phenol or liquid nitrogen has been recommended to destroy the remaining tumour cells after curettage, and filling of the defect with methylmethacrylate cement has been advocated. Between 1957 and 1992 we treated 92 patients with a GCT with 50% aqueous zinc chloride solution and bone grafting. Their mean age at the time of surgery was 31 years (15 to 59) and the mean follow-up was 11 years (5 to 31). Twelve (13%) had a local recurrence and one had a wound infection. Two developed degenerative changes around the knee. Eighty-six (93%) achieved good or excellent function. Three had moderate function, and three needed amputation. Our findings indicate that treatment with an aqueous solution of zinc chloride and reconstructive bone grafting after curettage gives good results


The Journal of Bone & Joint Surgery British Volume
Vol. 54-B, Issue 2 | Pages 216 - 229
1 May 1972
McGrath PJ

1. Fifty-five giant-cell tumours of bone are described in fifty-two patients of whom thirty-five were women. The highest incidence was in the third and fourth decades. 2. The tumours were characteristic radiologically: they all occurred in skeletally mature patients, and chiefly in the expanded extremities of long bones. 3. Histological grading was not done, the tumours being designated typical or malignant. 4. Curettage and graft, resection, radiotherapy and amputation were the basic forms of treatment. Amputation has an occasional place in primary treatment and radiotherapy should be confined to tumours in surgically inaccessible sites. 5. Resection is the method of choice for tumours in suitable sites, such as the upper end of the fibula ; careful curettage and grafting should be used to preserve the function of a large joint. 6. Recurrences within two years should be treated by limited resection without preliminary biopsy. Late recurrences must have a biopsy taken to establish the diagnosis before planning treatment


Orthopaedic Proceedings
Vol. 94-B, Issue SUPP_XXXVII | Pages 257 - 257
1 Sep 2012
Maric M Bergovec M Viskovic A Kolundzic R Smerdelj M Orlic D
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AIM. To present our experience in patients treated under primary diagnosis giant cell tumor of bone at Department Orthopaedic Surgery Zagreb University School of Medicine in a 15-year period from 1995 to 2009. METHODS. We performed a retrospective study of all patients treated in our Department because of giant cell tumor of bone (GCT) from 1995 to 2009. The mean age of our patients was 29,9 years (range: 14 to 70 years). Sex distribution showed prevalence in female (F:M=23:12=66%:34%). All together, 39 patients were operated under primary diagnosis of GCT. Four patients were lost in follow-up. In total, 35 patients were included in study. Diagnosis of GCT was made according to clinical, imaging and histological findings, and distributed by Campanacci's classification. RESULTS. Not including diagnostic biopsy, 84 operations were performed on 35 patients. Fourteen patients (40%) had GCT grade 1, fourteen (40%) had GCT grade 2, and seven (20%) had GCT grade 3. From the first symptoms to diagnosis there was an average duration of 7 months (range: 0 to 24 months), where the main symptoms were pain and swelling of affected bone and/or joint. GCT was localized in distal femur (n=12, 34%), proximal tibia (n=10, 29%), distal tibia (n=4, 11%), distal radius (n=3, 9%), and other locations (n=6, 17%). Patients with less aggressive GCT (grades 1 and 2) were treated with marginal excision: excochleation and reconstruction with bone transplant (n=12, 34%). In patients with locally more aggressive tumor (grades 2 and 3), “en bloc” resection and reconstruction with tumor endoprosthesis or bone transplant was performed (n=22, 63%). Due to localization of tumor, one patient was treated with radiation (3%). Complications were recorded in 12 patients (34%), and are shown as total number and percentage of all complications. Complications were the most common in knee region, proximal tibia (n=4, 33%) and distal femur (n=3, 25%). Also, the complications occured more frequently after “en bloc” resection (n=7, 58%). GCT classified as gradus 2 had most complications (n=5, 42%) till GCT classified as gradus 3 had least (n=3, 25% of complications, 9% of all). We recorded and treated local recurrence of tumor (n=6, 50%), infection (n=2, 17%), and mehanical complications of endoprosthesis (n=2, 17%). Due to local recurrences, in 2 patients underlying osteosarcoma was revealed, and they were treated with amputation. CONCLUSION. Each patient with GCT should be treated individually. Regardless non-malignant attribute, local behaviour of tumor determines treatment approach according to treatment principles of malignant tumor of bone. Number of complications in our patients is relatively high, recorded in one third of our patients, which matches the literature in announced studies


The Bone & Joint Journal
Vol. 100-B, Issue 12 | Pages 1626 - 1632
1 Dec 2018
Medellin MR Fujiwara T Tillman RM Jeys LM Gregory J Stevenson JD Parry M Abudu A

Aims. The aim of this paper was to investigate the prognostic factors for local recurrence in patients with pathological fracture through giant cell tumours of bone (GCTB). Patients and Methods. A total of 107 patients presenting with fractures through GCTB treated at our institution (Royal Orthopaedic Hospital, Birmingham, United Kingdom) between 1995 and 2016 were retrospectively studied. Of these patients, 57 were female (53%) and 50 were male (47%).The mean age at diagnosis was 33 years (14 to 86). A univariate analysis was performed, followed by multivariate analysis to identify risk factors based on the treatment and clinical characteristics. Results. The initial surgical treatment was curettage with or without adjuvants in 55 patients (51%), en bloc resection with or without reconstruction in 45 patients (42%), and neoadjuvant denosumab, followed by resection (n = 3, 3%) or curettage (n = 4, 4%). The choice of treatment depended on tumour location, Campanacci tumour staging, intra-articular involvement, and fracture displacement. Neoadjuvant denosumab was used only in fractures through Campanacci stage 3 tumours. Local recurrence occurred in 28 patients (25%). Surgery more than six weeks after the fracture did not affect the risk of recurrence in any of the groups. In Campanacci stage 3 tumours not treated with denosumab, en bloc resection had lower local recurrences (13%), compared with curettage (39%). In tumours classified as Campanacci 2, intralesional curettage and en bloc resections had similar recurrence rates (21% and 24%, respectively). After univariate analysis, the type of surgical intervention, location, and the use of denosumab were independent factors predicting local recurrence. Further surgery was required 33% more often after intralesional curettage in comparison with resections (mean 1.59, 0 to 5 vs 1.06, 0 to 3 operations). All patients treated with denosumab followed by intralesional curettage developed local recurrence. Conclusion. In patients with pathological fractures through GCTB not treated with denosumab, en bloc resection offers lower risks of local recurrence in tumours classified as Campanacci stage 3. Curettage or resections are both similar options in terms of the risk of local recurrence for tumours classified as Campanacci stage 2. The benefits of denosumab followed by intralesional curettage in these patients still remains unclear


Orthopaedic Proceedings
Vol. 92-B, Issue SUPP_III | Pages 440 - 440
1 Jul 2010
Balke M Neumann A Agelopoulos K Korsching E Hardes J Kersting C Buerger H Gosheger G Hagedorn M
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Because of the lack of a suitable in vivo model for giant cell tumors of bone little is known about their biological behavior and mechanisms of metastasis. No existing cell line contains all tumor components, so that testing of anti tumor agents is hardly possible. We therefore modified the chick chorio-allantoic membrane (CAM) assay for giant cell tumor of bone (GCTB). Out of tumor tissue obtained during surgery of 5 patients a solution was produced. The solute was grafted onto the CAM at day 10 of embryonic development. The growth process was monitored by daily observation and photo documentation using in vivo microscopy. After 5 to 6 days of tumor growth the samples were fixed in formalin and further analyzed using standard histology (hematoxylin and eosin stains). The tissue solute of all 5 patients formed solid tumors when grafted to the CAM. In vivo microscopy and standard histology revealed a rich vascularisation of the tumors. The tumors were composed of the typical components of GCTB including multinuclear giant cells. A reliable protocol for grafting of human giant cell tumors onto the chick chorio-allantoic membrane was established. This model is the first in vivo model for giant cell tumors of bone. Further characterization of the growing tissue is necessary in further experiments


Orthopaedic Proceedings
Vol. 92-B, Issue SUPP_III | Pages 440 - 440
1 Jul 2010
Gibbons C Jones F Taylor R Knowles H Hogendoorn P Wass J Balke3 M Gebert3 C Athanasou NA
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Giant cell tumour of bone (GCTB) is an expansile osteolytic tumour of bone which contains numerous osteoclast-like giant cells. GCTB is a locally aggressive tumour which can cause extensive bone destruction that can be difficult to control surgically, up to 35% of cases recurring after simple curettage. Bisphosphonates are anti-resorptive agents that have proved effective in the treatment of a number of osteolytic conditions. In keeping with its known effect on osteoclasts, we found that the aminobisphosphonate zoledronate abolished in vitro lacunar resorption in cultures of osteoclasts isolated from GCTB. The effect of zoledronate and other bisphosphonates on 15 cases of recurrent primary GCTB, four of which had metastasised to the lung, was assessed clinically. Most recurrent tumours did not exhibit progressive enlargement and, in some cases, both primary and metastatic GCTBs showed a degree of radiological improvement following treatment However, tumours did not diminish in size and, in some cases, no apparent treatment effect was noted. Our findings provide in vitro evidence for the use of bisphosphonates to inhibit the progressive osteolysis associated with GCTB. In vivo, these agents produced a degree of clinical and radiological improvement in some cases. This study reports results from three European centres where bisphosphonates are being used to treat recurrent GCTB and highlights the fact that these centres are all employing different clinical indications and different regimes of bisphosphonate treatment. Bisphosphonates have significant side effects and indications for treatment and standardisation of drug type and dosage regimes (and measurement of agreed outcome measures to determine treatment efficacy) should be established before these agents are included as part of a treatment protocol to control GCTB tumour growth and osteolysis


Orthopaedic Proceedings
Vol. 103-B, Issue SUPP_3 | Pages 64 - 64
1 Mar 2021
Aoude A Lim Z Perera J Ibe I Griffin A Tsoi K Ferguson P Wunder J
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Benign aggressive tumors are common and can be debilitating for patients especially if they are in peri-articular regions or cause pathological fracture as is common for giant cell tumor of bone (GCT). Although GCT rarely metastasize, the literature reports many series with high rates of local recurrence, and evidence about which risk factors influence recurrence is lacking. This study aims to evaluate the recurrence rate and identify local recurrence risk factors by reviewing patient data from a single high-volume orthopedic oncology center. A retrospective analysis of all patients treated for GCT at a tertiary orthopedic oncology center was conducted. In total 413 patients were treated for GCT between 1989 and 2017. Multiple patient and tumour characteristics were analysed to determine if they influenced local recurrence including: age, gender, anatomical site, Campanacci stage, soft tissue extension, presence of metastasis, pathologic fractures, and prior local recurrence. Additional variables that were analysed included type of treatment (en bloc resection or aggressive intralesional curettage) and use of local adjuvants. The main outcome parameters were local recurrence- free survival, metastasis-free survival and complications. Patients treated with Denosumab were excluded from analysis given its recently documented association with high rates of local recurrence. “There were 63/413 local recurrences (15.3%) at a mean follow-up of 30.5 months. The metastatic rate was 2.2% at a mean 50.6 months follow-up and did not vary based on type of treatment. Overall complication rate of 14.3% was not related to treatment modality. Local recurrence was higher (p=0.019) following curettage (55/310; 17.7%) compared to resection (8/103; 7.8%) however, joint salvage was possible in 87% of patients (270/310) in the curettage group. Use of adjuvant therapy including liquid nitrogen, peroxide, phenol, water versus none did not show any effect on local recurrence rates (p= 0.104). Pathological fracture did not affect local recurrence rates regardless of treatment modality (p= 0.260). Local recurrence at presentation was present in 16.3% (58/356) patients and did not show any significance for further local recurrence (p= 0.396). Gender was not associated with local recurrence (p=0.508) but younger patient age, below 20 years (p = 0.047) or below 30 years (p = 0.015) was associated with higher local recurrence rates. GCT in distal radius demonstrated the highest rate of local recurrence at 31.6% compared to other sites, although this was not significant (p=0.098). In addition, Campanacci stage and soft tissue extension were not risk factors for recurrence. The overall GCT local recurrence rate was 15.3%, but varied based on the type of resection: 17.7% following joint sparing curettage compared to 7.8% following resection. Local recurrence was also higher with younger patient age (30 years or less) and in distal radius lesions. In addition, neither Campanacci stage, soft tissue extension or presence of a pathologic fracture affected local recurrence. Most patients with GCT can undergo successful curettage and joint sparing, while only a minority require resection +/− prosthetic reconstruction. Even in the presence of soft tissue extension or a pathologic fracture, most joints can be salvaged with curettage


The Journal of Bone & Joint Surgery British Volume
Vol. 92-B, Issue 10 | Pages 1475 - 1479
1 Oct 2010
Gortzak Y Kandel R Deheshi B Werier J Turcotte RE Ferguson PC Wunder JS

Various chemicals are commonly used as adjuvant treatment to surgery for giant-cell tumour (GCT) of bone. The comparative effect of these solutions on the cells of GCT is not known. In this study we evaluated the cytotoxic effect of sterile water, 95% ethanol, 5% phenol, 3% hydrogen peroxide (H. 2. O. 2. ) and 50% zinc chloride (ZnCI. 2. ) on GCT monolayer tumour cultures which were established from six patients. The DNA content, the metabolic activity and the viability of the cultured samples of tumour cells were assessed at various times up to 120 hours after their exposure to these solutions. Equal cytotoxicity to the GCT monolayer culture was observed for 95% ethanol, 5% phenol, 3% H. 2. O. 2. and 50% ZnCI. 2. The treated samples showed significant reductions in DNA content and metabolic activity 24 hours after treatment and this was sustained for up to 120 hours. The samples treated with sterile water showed an initial decline in DNA content and viability 24 hours after treatment, but the surviving cells were viable and had proliferated. No multinucleated cell formation was seen in these cultures. These results suggest that the use of chemical adjuvants other than water could help improve local control in the treatment of GCT of bone


Orthopaedic Proceedings
Vol. 91-B, Issue SUPP_II | Pages 252 - 252
1 May 2009
Rabinovich A Thornhill O Colterjohn N Cowan R Ghert M Simunovic N Singh G
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Giant cell tumor (GCT) of bone is an osteolytic tumor that is locally aggressive and potentially metastatic. The pathogenesis of GCT is poorly understood. The purpose of this study was to harvest and culture primary cell lines from clinical specimens of GCT of bone and identify specific bone degradation proteases (matrix metalloproteinases: MMP-2, MMP-9) produced by the neoplastic stromal cells in vitro. With approval by the McMaster University Biohazards and Ethics Review Boards, we acquired consent from five patients with GCT of bone, and harvested specimens intraoperatively. The specimens were chopped in DMEM containing 10% Fetal Bovine Serum, 2 mM L-glutamine, 100 U/ml penicillin and 100 mg/ml streptomycin. The cell suspensions were incubated at thirty-seven degrees (5% CO2 and 95% air) and cultivated. The cells were grown to confluence and taken through several passages until only proliferative cells were present. Immunocytochemistry with TRAP (Tartrate Resistant Acid Phosphatase) was used to confirm the stem cell origin of the propagative cells. Protein electrophoresis with embedded gelatin was used for detecting protease activity (MMP-2, MMP-9) on cell lysates and medium. P-aminophenyl mercuric acetate (APMA) was used to activate and ethylenediaminetetraacetic acid (EDTA) was used to block MMP-2 and MMP-9 activity. Our controls included serum free media, Human Osteosarcoma and Fibroblast cell lines. Immunocytochemistry with TRAP confirmed that our propagative cells were not hematopoietic in origin but rather mesenchymal. Protein electrophoresis on cell lysates and medium identified the protease activity of MMP-2 and MMP-9 with lytic bands at appropriate molecular weights. APMA activated MMP-2 more than MMP-9, as indicated by increased relative density of bands. EDTA blocked the activity of both MMPs. Our study confirmed the ability to cultivate the neoplastic stromal cells of GCT of bone from clinical specimens. Protein electrophoresis showed that activated MMP-2 and MMP-9 are secreted from the neoplastic stromal cells in vitro, suggesting a role for the tumor cells in bone destruction. These results are intriguing, as novel therapies in specific MMP inhibitors are currently underway for numerous disease processes


Orthopaedic Proceedings
Vol. 94-B, Issue SUPP_XXXVII | Pages 302 - 302
1 Sep 2012
Van Der Heijden L Van De Sande M Nieuwenhuijse M Dijkstra P
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Background. Giant cell tumours of bone (GCT) are benign bone tumours with a locally aggressive character. Local recurrence is considered the main complication of surgical treatment and is described in up to 50% of patients. Intralesional curettage with the use of adjuvants like phenol or polymethylmetacrylate (PMMA) is recommended as initial treatment, significantly decreasing the risk of recurrence. However, risk factors for local recurrence in skeletal GCT have not yet been firmly established and a golden standard for local therapy remains controversial. Objective. The identification of risk factors predisposing for an increased risk of local recurrence. In addition, different surgical techniques are compared to identify the optimal surgical approach for the identified risk factors. Methods. In a retrospective study all 215 patients with bone GCT treated between 1964 and 2009 in one centre were included, of which 193 were suitable for analysis. All patients had minimal follow-up of 12 months (mean 115; range 12–445). Using a Kaplan Meier survival analysis recurrence free survival rates were calculated. Cox-regression was used to determine the influence of different types of therapy, the use of adjuvants, and various patient and tumour characteristics. Results. The mean local recurrence rate for all patients was 35.2% (n=68, 95%CI: 28.3–42.1). Recurrence rate after wide resection was 0.17 (n=6, 95%CI: 0.04–0.29), after curettage with adjuvants 0.32 (n=42, 95%CI 0.24–0.41) and after curettage alone 0.74 (n=20, 95%CI: 0.57–0.91, p < 0.001). Soft tissue extension (Hazard Ratio: 3.8, p < 0.001), localisation in radius and ulna (HR: 2.6, p=0.013), and surgical experience (HR: 2.2, p=0.022) were identified as significant general risk factors for local recurrence. For intralesional resection, Campanacci grade III (HR: 3.9, p=0.019) and location in axial skeleton (HR: 3.3, p=0.016) additionally significantly increased this risk. Comparing treatments our data showed that curettage followed by adjuvants was superior to curettage alone (p < 0.004), and the application of both phenol and PMMA did not present a significantly better outcome than curettage and PMMA alone (HR: 1.07, p=0.881). Conclusion. Of all possible risk factors only soft tissue extension, localisation in radius and ulna and non-radical resections significantly influenced the risk of local recurrence for all treatments. In addition, we found that high-grade tumours and localisation in the axial skeleton were additional risk factors for local recurrence after intralesional surgery. Although wide resection increases patient morbidity, it can be the therapy of choice in high risk patients. Intralesional therapy can be advised for low recurrence risk patients using curettage and PMMA only, whereas our study could not confirm the predicted effect of phenol as an additional adjuvant


The Journal of Bone & Joint Surgery British Volume
Vol. 79-B, Issue 1 | Pages 26 - 30
1 Jan 1997
Remedios D Saifuddin A Pringle J

We have reviewed 13 operations on 11 patients using curettage and polymethylmethacrylate cement for giant-cell tumour of bone (GCT) to assess the value of radiology in the early detection of recurrence. There were four recurrences, the most specific radiological sign on plain radiography was lysis of 5 mm or more at the cement-bone interface. This preceded clinical signs by a mean of four months and was identified at a mean of 3.75 months after operation. There was not always a complete sclerotic margin around the cement, but when it was present, there was never evidence of recurrence. MRI was helpful in assessing cases with evidence of recurrence. Frequent surveillance with plain radiography should continue for one year after operation irrespective of clinical signs of recurrence. When the appearance of the plain radiographs suggests recurrence, MRI should be performed and followed by image-guided needle biopsy


Orthopaedic Proceedings
Vol. 84-B, Issue SUPP_III | Pages 304 - 304
1 Nov 2002
Robinson D Dotan A Nevo Z
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Objectives: Development a giant cell tumor model arising from the mutated mesenchymal cells present in its stroma. This establishes the pathogenic mechanism of giant cell tumor, and allows the evaluation of the possible role of biphosphonates and retinoic acid in medical therapy of giant cell tumor of bone. Introduction: In previous studies our group has shown that mesenchymal stroma contains mesenchymal cells capable of recruiting osteoclasts, and lacking capacity to undergo osteoblastic differentiation. These cells represent the actual neoplastic component of the tumor. In the current study, an attempt was made to establish a giant cell tumor in an animal model by injection of these cells. Methods: 6 Balb/C named mice were used. The mice were kept in a laminar flow hood and injected when they were 4 weeks old. The injection was in an intra-osseous location into the distal femur. The cell inoculum consisted of 1 million stromal cells. The cells were derived from a grade III giant cell tumor occurring in the hip joint of a 30 years old woman. The mice were kept for 2 months and than sacrificed. Results: A lytic lesion similar to that occurring in humans developed. The tumor consisted of stromal cells with interspersed osteoclasts. These were identified as being of host origin by mice-specific monoclonal antibodies. The tumor penetrated the cortex but did not infiltrate the articular cartilage. Metastases were not observed. Discussion: Giant cell tumor of bone is typified by osteolytic bone destruction mediated by osteoclasts. In previous studies, our group has shown that the proliferation rate of the stromal component correlates closely with prognosis and grade of the tumor. The stromal component was shown to consist of pre-osteoblasts that fail to differentiate into osteoblasts, but instead recruit giant cells (osteoclasts), mediating bone destruction. Addition of retinoic acid in culture induces osteoblastogenesis cells by blocking AP-1. The current study confirms in an animal model that indeed the stromal cells are capable of osteoclast recruitment and bone destruction. This animal model might allow development of medical remedies to this tumor


The Journal of Bone & Joint Surgery British Volume
Vol. 80-B, Issue 1 | Pages 43 - 47
1 Jan 1998
Siebenrock KA Unni KK Rock MG

We reviewed 23 patients with a giant-cell tumour (GCT) of bone and histologically-proven lung metastases at a mean of 11.9 years (3 to 24.5) after the original diagnosis. The mean age of the patients at diagnosis was 27.3 years (9 to 61); the male to female ratio was 0.9:1. The most common primary site was the distal radius. The mean interval between the onset of the tumour and the detection of lung metastases was 4.1 years (0 to 24). There had been local recurrence in 19 (83%) either before or at the time of diagnosis of lung metastasis. Surgical resection alone was the preferred treatment for lung metastases in 70% and resulted in 18 patients (76%) being free from disease when last reviewed. One patient had the spontaneous regression of lung metastases and was free from recurrence 16 years later. Sixteen patients (69.7%) have survived and four (17.4%) have died from progression of the tumour. Three other deaths were not related to the tumour. Local recurrence and a primary lesion at the distal radius seem to be associated with an increased risk of lung metastases. Repeated surgical resection of lung metastases gave a high rate of survival


Orthopaedic Proceedings
Vol. 92-B, Issue SUPP_III | Pages 443 - 443
1 Jul 2010
Penna V Babeto E Toller E Becker R Pinheiro C Pires L Valsechi M Kerr L Peitl P Rahal P Morini S
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The giant cell tumor of bone (GCT) is a locally aggressive intraosseous neoplasm, with an uncertain biological behavior, constituted of giant multinuclear cells spread over tumoral tissue with a nucleus presenting the same features of the ovoid and fusiform cells forming its stroma. The local recurrence of GCT is often observed, mainly in the first three years after treatment, giving a rate of recurrence ranging in 20 to 50% of cases. Further aggravating the recurrence is the fact that after the relapse, the patient often also presents metastases in other organs. The aim of this study was to identify and to characterize differentially expressed genes that can be used in the prognostic, treatment and understanding of this physiopathology. To identify novel genes differentially expressed in GCT, we have applied rapid subtractive hybridization (RaSH). Samples of GCT and normal tissues were obtained at Tumor Bank of Barretos Cancer Hospital. After RNA extraction and cDNA synthesis the samples were submitted to Rapid hybridization Subtraction (RaSH) methodology for subtractive libraries elaboration. The RaSH subtractive libraries reveals the presence of 619 different clones including both normal and tumor tissues were identified. Of these, 450 in tumor sample and 169 in control tissue. Four biomarkers candidates were selected for validation: ZAK, KTN1, NEB, and ROCK1 genes, whose functions are, related to cell cycle checkpoint, transport of organelles, cytoskeletal matrix and cell adhesions. The validation of selected differentially expressed genes was performed using real time PCR. The putative molecular markers found in this work may help to find the basis for a molecular comprehension of GCT, thus improving diagnosis, treatment and outcome for patients with this tumor


Orthopaedic Proceedings
Vol. 94-B, Issue SUPP_XXX | Pages 4 - 4
1 Jul 2012
van de Sande M van der Heijden L Gibbons M Dijkstra P
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Introduction. Local recurrence of Giant cell tumours of bone (GCT) is considered the main complication of surgical treatment (50%). Intra-lesional curettage with adjuvants like phenol or polymethylmethacrylate (PMMA) is recommended as initial treatment, decreasing the risk of recurrence. However, risk factors for local recurrence in skeletal GCT have not yet been firmly established and a golden standard for treatment remains controversial. Aim of this study is identification of risk factors for recurrence in GCT, specifically after intra-lesional curettage with or without adjuvants. Methods. In a retrospective single-institution study 191 patients treated for GCT between 1964 and 2009 were included. Mean follow-up was 111 months (range 12-415). The recurrence-free survival and hazards for different treatment strategies and various patient and tumour characteristics were determined. Results. Overall risk of recurrence was 36.1% (n=66, 95% CI: 28.3-42.1). Recurrence rate after wide resection was 20%, after curettage with adjuvants 33% and after curettage alone 77%. Hogendoorn-grade III (Hazard Ratio: 5.7, p⋋0.001), localisation in axial skeleton (HR: 3.7, p⋋0,001), primary treatment in a non-specialised centre (HR: 2.8, p⋋0.001) and extension into soft tissue (HR: 2.0, p=0.02) were significant risk factors for local recurrence. Curettage with adjuvants proved superior to curettage alone (p⋋0.004 p=0.07, HR: 0.54), but the application of both PMMA and phenol did not present a significantly better outcome than PMMA alone (HR: 1.07, p=0.9). Discussion. Of all possible risk factors only soft tissue extension and localisation in distal radius significantly influenced the risk of local recurrence for all treatments. We found that high-grade tumours and localisation in the axial skeleton were additional risk factors for local recurrence after intra-lesional surgery. Although wide resection increases morbidity, it can be the therapy of choice in high risk patients. Intra-lesional therapy can be advised for low risk patients using curettage adjuvants and PMMA