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1.  The Clinical Approach Toward Giant Cell Tumor of Bone 
The Oncologist  2014;19(5):550-561.
The authors provide an overview of imaging, histopathology, genetics, and multidisciplinary treatment of giant cell tumor of bone (GCTB), an intermediate, locally aggressive but rarely metastasizing tumor. This review addresses most relevant issues concerning diagnosis and multidisciplinary treatment of GCTB and future perspectives.
We provide an overview of imaging, histopathology, genetics, and multidisciplinary treatment of giant cell tumor of bone (GCTB), an intermediate, locally aggressive but rarely metastasizing tumor. Overexpression of receptor activator of nuclear factor κB ligand (RANKL) by mononuclear neoplastic stromal cells promotes recruitment of numerous reactive multinucleated giant cells. Conventional radiographs show a typical eccentric lytic lesion, mostly located in the meta-epiphyseal area of long bones. GCTB may also arise in the axial skeleton and very occasionally in the small bones of hands and feet. Magnetic resonance imaging is necessary to evaluate the extent of GCTB within bone and surrounding soft tissues to plan a surgical approach. Curettage with local adjuvants is the preferred treatment. Recurrence rates after curettage with phenol and polymethylmethacrylate (PMMA; 8%–27%) or cryosurgery and PMMA (0%–20%) are comparable. Resection is indicated when joint salvage is not feasible (e.g., intra-articular fracture with soft tissue component). Denosumab (RANKL inhibitor) blocks and bisphosphonates inhibit GCTB-derived osteoclast resorption. With bisphosphonates, stabilization of local and metastatic disease has been reported, although level of evidence was low. Denosumab has been studied to a larger extent and seems to be effective in facilitating intralesional surgery after therapy. Denosumab was recently registered for unresectable disease. Moderate-dose radiotherapy (40–55 Gy) is restricted to rare cases in which surgery would lead to unacceptable morbidity and RANKL inhibitors are contraindicated or unavailable.
PMCID: PMC4012970  PMID: 24718514
Giant cell tumor of bone; GCTB; Denosumab; Radiotherapy; RANK ligand; Curettage; Histopathology; Review
2.  Giant-cell tumor of bone, anti-RANKL therapy 
BoneKEy Reports  2012;1:149.
Giant-cell tumor of bone (GCTB) is a rare osteolytic tumor of the bone. Although classified as a benign tumor, GCTB is characterized by local aggressiveness and risk of local recurrence. In addition, GTCB can in some cases lead to the development of so-called 'benign' chest metastases. Surgical resection by intralesional curettage with high-speed burring and polymethylmethacrylate cement is the standard treatment for resectable tumors. In cases of metastatic or unresectable disease (when planned surgical procedure is impossible or would result in severe morbidity), medical treatments such as cytotoxic chemotherapy or interferon-α have limited efficacy. Bisphosphonates have been proposed as a therapeutic option to reduce osteoclast activity. In bone, various pathological states may result from an imbalance in the RANK (receptor activator of nuclear factor kappa-B)/RANKL (receptor activator of nuclear factor kappa-B ligand)/OPG (osteoprotegerin) pathway. Involvement of the RANKL pathway in pathogenesis of GCTB was first proposed in 2000. Denosumab is a fully human monoclonal antibody that binds and inhibits RANKL, thereby preventing the activation of the RANK pathway. As it showed the possibility to counteract osteoclast activation in GCTB and prevent the known physiopathological role of RANKL, denosumab has been under evaluation in the clinic as a treatment for GCTB since 2005. Results of a first Phase II trial demonstrate the therapeutic potential of denosumab to inhibit progressive bone destruction and metastatic progression in patients with unsalvageable giant-cell tumor (GCT), and have also provided key insights into the biology of GCT. Denosumab is currently a therapeutic option for patients with unresectable GCTB but its place in the global therapeutic strategy has not yet been defined.
PMCID: PMC3868728  PMID: 24363925
3.  Recurrent Giant Cell Tumor of Long Bones: Analysis of Surgical Management 
Treatment of giant cell tumor of bone (GCT) often is complicated by local recurrence. Intralesional curettage is the standard of care for primary GCTs. However, there is controversy whether intralesional curettage should be preferred over wide resection in recurrent GCTs.
We investigated the rerecurrence-free survival after surgical treatment of recurrent GCTs to determine the influence of the surgical approach, adjuvant treatment, local tumor presentation, and demographic factors on the risk of further recurrence.
Patients and Methods
We retrospectively reviewed the medical records of 46 patients with recurrent GCTs of long bones treated with wide resection or intralesional curettage and compared these cohorts. Recurrence rates, risk factors for recurrence, and the development of pulmonary metastases were determined. The minimum followup was 37 months (mean, 134 months; range, 37–337 months).
The rate of rerecurrence after wide resection was 6%. Intralesional curettage showed an overall rerecurrence rate of 32%. Implantation of polymethylmethacrylate (PMMA) instead of bone grafting was associated with a lower risk of subsequent recurrence in intralesional procedures (14% versus 50%). Extracompartmental disease did not increase the risk of rerecurrence. Pulmonary metastases occurred in seven patients and appeared independent of the surgical treatment modality chosen.
Intralesional curettage with methylmethacrylate for recurrent GCT provided equivalent tumor control compared with resection in this retrospective study. If joint salvage is possible, we advocate this treatment over resection in recurrent GCTs to preserve the native joint articulation.
Level of Evidence
Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC3048273  PMID: 20857250
4.  Giant Cell Tumor With Pathologic Fracture: Should We Curette or Resect? 
Approximately one in five patients with giant cell tumor of bone presents with a pathologic fracture. However, recurrence rates after resection or curettage differ substantially in the literature and it is unclear when curettage is reasonable after fracture.
We therefore determined: (1) local recurrence rates after curettage with adjuvants or en bloc resection; (2) complication rates after both surgical techniques and whether fracture healing occurred after curettage with adjuvants; and (3) function after both treatment modalities for giant cell tumor of bone with a pathologic fracture.
We retrospectively reviewed 48 patients with fracture from among 422 patients treated between 1981 and 2009. The primary treatment was resection in 25 and curettage with adjuvants in 23 patients. Minimum followup was 27 months (mean, 101 months; range, 27–293 months).
Recurrence rate was higher after curettage with adjuvants when compared with resection (30% versus 0%). Recurrence risk appears higher with soft tissue extension. The complication rate was lower after curettage with adjuvants when compared with resection (4% versus 16%) and included aseptic loosening of prosthesis, allograft failure, and pseudoarthrosis. Tumor and fracture characteristics did not increase complication risk. Fracture healing occurred in 24 of 25 patients. Mean Musculoskeletal Tumor Society score was higher after curettage with adjuvants (mean, 28; range, 23–30; n = 18) when compared with resection (mean, 25; range, 13–30; n = 25).
Our observations suggest curettage with adjuvants is a reasonable option for giant cell tumor of bone with pathologic fractures. Resection should be considered with soft tissue extension, fracture through a local recurrence, or when structural integrity cannot be regained after reconstruction.
Level of Evidence
Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC3563806  PMID: 22926445
5.  Expression of ezrin, CD44, and VEGF in giant cell tumor of bone and its significance 
This research aimed to study the role of ezrin, CD44, and VEGF in invasion, metastasis, recurrence, and prognosis of giant cell tumor of bone (GCTB) and its association with the clinical and pathological features of GCTB.
Expression status of ezrin, CD44, and VEGF in 80 GCTB tissues and its adjacent noncancerous tissue samples were measured with immunohistochemical and Elivison staining. Their correlation with the clinical and pathologic factors was statistically analyzed by chi-square test.
The expression status of ezrin, CD44, and VEGF were significantly higher in GCTB tissue samples than in its adjacent noncancerous tissue samples and in GCTB at Campanacci stage III than in Campanacci stages I and II (P < 0.05). No significant difference was found in age and sex of the patients and locations of the tumor (P > 0.05). Survival analysis showed that the expression status of ezrin, CD44, VEGF, and Campanacci clinical stages of GCTB were positively associated with the survival rate of GCTB patients and negatively associated with ezrin and Campanacci stages of GCTB, indicating that ezrin, CD44, VEGF, and Campanacci clinical stages of GCTB are the independent factors for GCTB.
Ezrin, CD44, and VEGF are over-expressed in GCTB tissue and its adjacent noncancerous tissue samples and may play an important role in the occurrence, invasion, metastasis, and recurrence of GCTB. Measurement of ezrin, CD44, and VEGF expression status may contribute to the judgment of prognosis of GCTB patients.
PMCID: PMC4434870  PMID: 25929323
Giant cell tumor of bone; Ezrin; CD44; VEGF; Prognosis
6.  Which Treatment is the Best for Giant Cell Tumors of the Distal Radius? A Meta-analysis 
Intralesional excision and en bloc resection are used to treat giant cell tumors (GCTs) of the distal radius. However, it is unclear whether one provides lower rates of recurrences and fewer complications, and whether the use of polymethylmethacrylate (PMMA) after curettage reduces the risk of recurrence.
We examined whether curettage was associated with lower rates of recurrence and fewer major complications compared with en bloc excision, and whether PMMA resulted in lower rates of recurrence compared with a bone graft.
We systematically searched the literature using the criteria, “giant cell tumor” AND “curettage” OR “intralesional excision” OR “resection”. Six relevant articles were identified that reported data for 80 curettage cases (PMMA, n = 49; bone graft, n = 26; no PMMA or bone grafts, n = 5) and 59 involving en bloc excision. A meta-analysis was performed using these data.
Overall, patients in the intralesional excision group had a higher recurrence rate (relative risk [RR], 2.80; 95% CI, 1.17–6.71), especially for Campanacci Grade 3 GCTs (RR, 4.90; 95% CI, 1.36–17.66), yet fewer major complications (RR, 0.21; 95% CI, 0.09–0.54) than the en bloc resection group. The use of PMMA versus bone graft did not affect the recurrence rate (RR, 0.98; 95% CI, 0.44–2.17).
Based on data obtained from the limited number of studies available, intralesional excision appears to be more appropriate for the treatment of local lesions (eg, Grades 1 and 2) than Grade 3 GCTs of the distal radius. Moreover, PMMA was not additionally effective as an adjuvant.
Level of Evidence
Level III, therapeutic study (systematic review). See Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC3442009  PMID: 22773395
7.  Pulmonary metastasis of giant cell tumor of bones 
Giant cell tumor of bone (GCTB) accounts for 5% of primary skeletal tumors. Although it is considered to be a benign lesion, there are still incidences of pulmonary metastasis. Pulmonary metastasis of GCTB may be affected by tumor grading and localization as well as the age, gender and overall health status of the patient. Patients with local recurrence are more likely to develop pulmonary metastasis of GCTB. High expression of some genes, cytokines and chemokines may also be closely related to the metastatic potential and prognosis of GCTB. The treatment of the primary GCTB is key to the final outcome of the disease, as intralesional curettage has a significantly higher local recurrence and pulmonary metastasis rate than wide resection. However, even patients with pulmonary metastasis seem to have a good prognosis after timely and appropriate surgical resection. It is hoped that with the development of novel surgical methods and drugs, pulmonary metastasis of GCTB can be prevented and treated more effectively.
PMCID: PMC4155080  PMID: 25139054
Giant cell tumor; Bone; Pulmonary metastasis
8.  Giant Cell Tumor of Bone: Risk Factors for Recurrence 
Many surgeons treat giant cell tumor of bone (GCT) with intralesional curettage. Wide resection is reserved for extensive bone destruction where joint preservation is impossible or when expendable sites (eg, fibular head) are affected. Adjuvants such as polymethylmethacrylate and phenol have been recommended to reduce the risk of local recurrence after intralesional surgery. However, the best treatment of these tumors and risk factors for recurrence remain controversial.
We evaluated the recurrence-free survival after surgical treatment of GCT to determine the influence of the surgical approach, adjuvant treatment, local tumor presentation, and demographic factors on the risk of recurrence.
We retrospectively reviewed 118 patients treated for benign GCT of bone between 1985 and 2005. Recurrence rates, risk factors for recurrence and the development of pulmonary metastases were determined. The minimum followup was 36 months (mean, 108.4 ± 43.7; range, 36–233 months).
Wide resection had a lower recurrence rate than intralesional surgery (5% versus 25%). Application of polymethylmethacrylate decreased the risk of local recurrence after intralesional surgery compared with bone grafting; phenol application alone had no effect on the risk of recurrence. Pulmonary metastases occurred in 4%; multidisciplinary treatment including wedge resection, chemotherapy, and radiotherapy achieved disease-free survival or stable disease in all of these patients.
We recommend intralesional surgery with polymethylmethacrylate for the majority of primary GCTs. Because pulmonary metastases are rare and aggressive treatment of pulmonary metastases is usually successful, we believe the potential for metastases should not by itself create an indication for wide resection of primary tumors.
Level of Evidence
Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC3018195  PMID: 20706812
9.  Contemporary adjuvant polymethyl methacrylate cementation optimally limits recurrence in primary giant cell tumor of bone patients compared to bone grafting: a systematic review and meta-analysis 
Reports of recurrence following restructuring of primary giant cell tumor (GCT) defects using polymethyl methacrylate (PMMA) bone cementation or allogeneic bone graft with and without adjuvants for intralesional curettage vary widely. Systematic review and meta-analysis were conducted to investigate efficacy of PMMA bone cementation and allogeneic bone grafting following intralesional curettage for GCT.
Medline, EMBASE, Google Scholar, and Cochrane databases were searched for studies reporting GCT of bone treatment with PMMA cementation and/or bone grafting with or without adjuvant therapy following intralesional curettage of primary GCTs. Pooled risk ratios and 95% confidence intervals (CIs) for local recurrence risks were calculated by fixed-effects methods.
Of 1,690 relevant titles, 6 eligible studies (1,293 patients) spanning March 2008 to December 2011 were identified in published data. Treatment outcomes of PMMA-only (n = 374), bone graft-only (n = 436), PMMA with or without adjuvant (PMMA + adjuvant; n = 594), and bone graft filling with or without adjuvant (bone graft + adjuvant; n = 699) were compared. Bone graft-only patients exhibited higher recurrence rates than PMMA-treated patients (RR 2.09, 95% CI (1.64, 2.66), Overall effect: Z = 6.00; P <0.001), and bone graft + adjuvant patients exhibited higher recurrence rates than PMMA + adjuvant patients (RR 1.66, 95% CI (1.21, 2.28), Overall effect: Z = 3.15, P = 0.002).
Local recurrence was minimal in PMMA cementation patients, suggesting that PMMA is preferable for routine clinical restructuring in eligible GCT patients. Relationships between tumor characteristics, other modern adjuvants, and recurrence require further exploration.
PMCID: PMC3717274  PMID: 23866921
Giant cell tumors; Recurrence; Polymethyl methacrylate; Cementation; Bone grafting
10.  Surgical Downstaging in an Open-Label Phase II Trial of Denosumab in Patients with Giant Cell Tumor of Bone 
Annals of Surgical Oncology  2015;22(9):2860-2868.
Surgical resection with curative intent for giant cell tumor of bone (GCTB) may be associated with severe morbidity. This interim analysis evaluated reduction in surgical invasiveness after denosumab treatment in patients with resectable GCTB.
Patients with primary or recurrent GCTB, for whom the initially planned surgery was associated with functional compromise or morbidity, received denosumab 120 mg subcutaneously every 4 weeks (additional doses on days 8 and 15 of the first cycle). Planned and actual GCTB-related surgical procedures before and after denosumab treatment were reported. Patients were followed for surgical outcome, adverse events, and recurrence following resection.
Overall, 222 patients were evaluable for surgical downstaging (54 % were women; median age 34 years). Lesions (67 % primary and 33 % recurrent) were located in the axial (15 %) and appendicular skeleton (85 %). At the data cutoff date, most patients had not yet undergone surgery (n = 106; 48 %) or had a less morbid procedure (n = 84; 38 %) than originally planned. Median (interquartile range) time on denosumab was 19.5 (12.4–28.6) months for the 106 patients who had not undergone surgery and were continuing on monthly denosumab. Native joint preservation was 96 % (n = 24/25) for patients with planned joint/prosthesis replacement and 86 % (n = 30/35) for patients with planned joint resection/fusion. Of the 116 patients who had surgery (median postsurgical follow-up 13.0 [8.5–17.9] months), local recurrence occurred in 17 (15 %) patients.
For patients with resectable GCTB, neoadjuvant denosumab therapy resulted in beneficial surgical downstaging, including either no surgery or a less morbid surgical procedure.
Electronic supplementary material
The online version of this article (doi:10.1245/s10434-015-4634-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4531146  PMID: 26033180
11.  Local control of giant cell tumors of the long bone after aggressive curettage with and without bone cement 
Aggressive curettage has been well established for the treatment of giant cell tumors (GCTs) of the bone. The purpose of this study was to review our experience and evaluate the role of different implant materials in patients with GCTs of the extremities after aggressive curettage.
A total of 119 patients with GCTs of the long bone were treated at the First Affiliated Hospital of Sun Yat-Sen University between 2004 and 2009. We excluded patients presenting metastases, recurrent tumors, and soft tissue involvement and those with Jaffe pathological grade III. The remaining 65 patients were treated with aggressive curettage using a bone graft or bone cement to fill the cavity. The recurrence rates and functional scores associated with the different fillings were analyzed.
Aggressive curettage and bone grafting was performed in 34 cases (52.3%), and aggressive curettage with bone cement was performed in 31 cases (47.7%). The overall recurrence rate after the aggressive intralesional procedures was 35.3% with bone grafting and 12.9% when bone cement was used as an adjuvant filling. The recurrence rate following aggressive curettage and bone grafting was higher than that following aggressive curettage with cement (p = 0.038). The Musculoskeletal Tumor Society (MSTS) score for bone graft patients was 91.1%, which was significantly lower than that for patients treated with bone cement (94.7%).
The use of bone cement was associated with a significantly lower recurrence rate than bone grafting following aggressive intralesional curettage to treat benign giant cell tumors of the long bone. Better MSTS functional results were also observed in the bone cement group compared to the bone graft group.
PMCID: PMC4196200  PMID: 25277133
Giant cell tumor of the long bone; Bone graft; Bone cement; Aggressive curettage; Local recurrence
12.  Treatment and outcome of giant cell tumors of the pelvis 
Acta Orthopaedica  2009;80(5):590-596.
Background and purpose Giant cell tumors (GCTs) of bone rarely affect the pelvis. We report on 20 cases that have been treated at our institution during the last 20 years.
Methods 20 patients with histologically benign GCT of the pelvis were included in this study. 9 tumors were primarily located in the iliosacral area, 6 in the acetabular area, and 5 in the ischiopubic area. 8 patients were treated by intralesional curettage and 6 by intralesional resection with additional curettage of the margins. 3 patients with iliacal tumors were treated by wide resection. 2 patients were treated by a combination of external beam irradiation and surgery, and 1 patient solely by irradiation. In addition, 9 patients received selective arterial embolization one day before surgery. Of the 6 patients with acetabular tumors, 1 secondarily received an endoprosthesis and 1 was primarily treated by hip transposition. The patients were followed for a median time of 3 (1–11) years.
Results 1 patient with a pubic tumor developed a local recurrence 1 year after intralesional resection and additional curettage of the margins. The recurrence presented as a small soft tissue mass within the scar tissue of the gluteal muscles and was treated by resection. No secondary sarcoma was detected and none of the patients developed pulmonary metastases or multicentricity. No major complication occurred during surgery.
Interpretation We conclude that most GCTs of the pelvis can be treated by intralesional procedures. For tumors of the iliac wing, wide resection can be an alternative. Surgical treatment of tumors affecting the acetabular region often results in functional impairment. Pre-surgical selective arterial embolization appears to be a safe procedure that may reduce the risk of local recurrence.
PMCID: PMC2823344  PMID: 19916695
13.  Prognostic Impact of Reduced Connexin43 Expression and Gap Junction Coupling of Neoplastic Stromal Cells in Giant Cell Tumor of Bone 
PLoS ONE  2015;10(5):e0125316.
Missense mutations of the GJA1 gene encoding the gap junction channel protein connexin43 (Cx43) cause bone malformations resulting in oculodentodigital dysplasia (ODDD), while GJA1 null and ODDD mutant mice develop osteopenia. In this study we investigated Cx43 expression and channel functions in giant cell tumor of bone (GCTB), a locally aggressive osteolytic lesion with uncertain progression. Cx43 protein levels assessed by immunohistochemistry were correlated with GCTB cell types, clinico-radiological stages and progression free survival in tissue microarrays of 89 primary and 34 recurrent GCTB cases. Cx43 expression, phosphorylation, subcellular distribution and gap junction coupling was also investigated and compared between cultured neoplastic GCTB stromal cells and bone marow stromal cells or HDFa fibroblasts as a control. In GCTB tissues, most Cx43 was produced by CD163 negative neoplastic stromal cells and less by CD163 positive reactive monocytes/macrophages or by giant cells. Significantly less Cx43 was detected in α-smooth muscle actin positive than α-smooth muscle actin negative stromal cells and in osteoclast-rich tumor nests than in the adjacent reactive stroma. Progressively reduced Cx43 production in GCTB was significantly linked to advanced clinico-radiological stages and worse progression free survival. In neoplastic GCTB stromal cell cultures most Cx43 protein was localized in the paranuclear-Golgi region, while it was concentrated in the cell membranes both in bone marrow stromal cells and HDFa fibroblasts. In Western blots, alkaline phosphatase sensitive bands, linked to serine residues (Ser369, Ser372 or Ser373) detected in control cells, were missing in GCTB stromal cells. Defective cell membrane localization of Cx43 channels was in line with the significantly reduced transfer of the 622 Da fluorescing calcein dye between GCTB stromal cells. Our results show that significant downregulation of Cx43 expression and gap junction coupling in neoplastic stromal cells are associated with the clinical progression and worse prognosis in GCTB.
PMCID: PMC4416750  PMID: 25933380
14.  Giant Cell Tumor of Bone: A Neoplasm or a Reactive Condition? 
Giant cell tumor of bone (GCTB) is a benign but locally aggressive bone tumor of young adults. It typically presents as a large lytic mass at the end of the epiphysis of long bones. Grossly it is comprised of cystic and hemorrhagic areas with little or no periosteal reaction. Microscopically areas of frank hemorrhage, numerous multinucleated giant cells and spindly stromal cells are present. Telomeric fusions, increased telomerase activity and karyotypic aberrations have been advanced as a proof of its neoplastic nature. However such findings are not universal and can be seen in rapidly proliferating normal cells as well as in several osseous lesions of developmental and/or reactive nature, and the true neoplastic nature of GCTB remains controversial. The ancillary studies have generally not reached to the point where these alone can be taken as sole diagnostic and discriminatory criteria. While giant cells and stromal cells have been extensively studied, little attention has been paid to the overwhelming hemorrhagic component. If examined carefully intact and partially degenerated red blood cells are almost invariably seen in many giant cells as well as in the stroma. While hemorrhage in many patients may be resolved without leaving any trace over time, in some it gives rise to giant cell formation, and in others it may lead to proliferation of fibroblasts and histiocytes. At times one sees xanthomatous cells due to intracytoplasmic cholesterol deposits and sharp cholesterol clefts. Individual genetic makeup, local tissue factors as well as the amount of hemorrhage may play a key role in the final effects and outcome. Malignancy usually does not occur in GCTB and when discover, it usually represents primary bone sarcomas missed at original diagnosis. Embolization therapy to curtail hemorrhage and insertion of cement substance to support matrix are helpful in reducing recurrences. Aneurysmal bone cyst (ABC) shares many features with GCTB. There had been unique karyotypic changes in some aneurysmal bone cysts making it distinct from GCTB. However these changes may be in the endothelial cells which are quite different from stromal or giant cells. It had been concluded that the poor matrix support to the vessels may lead to frequent and profuse intraosseous hemorrhage attracting blood-derived monocytes with active conversion into osteoclasts, resulting in GCTB formation. On the other hand, dilatation of the thin-walled blood vessels results in formation of ABCs. If hemorrhagic foci are replaced by proliferation of fibroblasts and histiocytes, then a picture of fibrous histiocytic lesion is emerged. Enhanced telomerase activity and karyotypic aberrations may be necessary for rapid division of the nuclei of the giant cells in order to be able to deal with significant in situ intraosseous hemorrhage.
PMCID: PMC2480584  PMID: 18787633
Giant cell tumor; bone; osteoclastoma; aneurysmal bone cyst; osteoclast; hemorrhage; bone matrix; telomerase
15.  Local recurrences after curettage and cementing in long bone giant cell tumor 
Indian Journal of Orthopaedics  2011;45(2):168-173.
Giant cell tumor of bone (GCT) is a benign lesion with great propensity for local recurrence. This study aimed to analyse the rates of local recurrence and its possible predisposing factors in Campanacci’s Grade III and II GCT of long bones following intralesional curettage and bone cementing.
Materials and Methods:
32 cases of either sex with Campanacci’s Grade II (n= 14), and Grade III (n=18) with intact articular surface, operated between 1995 and 2007 in form of intralesional curettage and bone cementing were studied. All the cases were followed up for 2.5-12 years (mean, 6.5), after primary treatment. The mean age at operation was 32.4 years (range, 18.5-40 years). The proximal tibia was involved in 13 cases (40.6%), followed by distal femur (n=11)34.4% distal tibia (n=3) 9.4%, proximal femur (n=2) 3.2% and distal radius (n=3) 9.4%.
Eleven patients (34.4%) had local recurrence, of which eight were of Campanacci’s Grade III. The mean recurrence time was 14 months (range, 3-34 months). The two-year recurrence-free survivorship was 71.9% (n=23/32). Post-recurrence mean follow-up was 4.2 years (range, 2-6.5 years).
We observed higher rate of local recurrence with Campanacci’s Grade III GCTs. We recommend selective use of this procedure in Grade III lesions, particularly with extensive soft tissue involvement.
PMCID: PMC3051125  PMID: 21430873
Bone cementing; GCT; recurrence
16.  Giant cell tumor of bone: Is curettage the answer? 
Indian Journal of Orthopaedics  2007;41(2):109-114.
Giant cell tumors (GCT) are neoplasms of mesenchymal stromal cells with varied manifestations. There is no uniform accepted treatment protocol for these tumors,
Materials and Methods:
49 cases of proven giant cell tumors of appendicular skeleton, 27 prospective and 22 retrospective constituteed this study. The retrospective cases were collected by using computerized data base collection method. The patients were evaluated clinically, radiologically and by histology. Companacci grading and Enneking staging was used in the study. Two treatment modalities were used a) extended curettage (with/ without bone grafting/ cementation) or b) wide excision and reconstruction with a prosthesis or arthrodesis. Functional evaluation was done by Enneking's system. Chi square tests, mann-whitney test and ANOVA were used for statistical analysis.
The average age was 26.82 years (16-50 years). 25 patients (51%) were recurrent GCT at presentation. The commonest site was lower end of femur (16 cases, 32.65%) and upper end of tibia (13 cases, 26.53%). 40 (81.63%) tumors had less than 5 mm of subchondral bone free of tumor. 35 (71.43%) tumors were Enneking's surgical stage III and companacci grade III. Pathological fractures were seen in 12 (24.49%) cases. Intra-lesional currettage was used in 28 and enbloc excision in 19 patients and 2 (4.08%) underwent amputation. The average follow up period was 18.6 months (range 2-84). One recurrence was seen in a grade III recurrent distal radial lesion in the intralesional curettage group (3.57%) Enneking's functional score with intralesional curettage (25.41) was better than enbloc excision (21.37). Enbloc excision had higher rates of infections (36.84 % Vs 25%) and soft tissue coverage problems (21.05% Vs 0).
Intralesional therapy has a better functional outcome and less complications than enbloc excision, albeit with a high recurrence rate which can however be effectively treated with repeat extended curettage.
PMCID: PMC2989132  PMID: 21139761
Adjuvant therapy; extended curettage; giant cell tumor
17.  Bisphosphonate treatment of aggressive primary, recurrent and metastatic Giant Cell Tumour of Bone 
BMC Cancer  2010;10:462.
Giant cell tumour of bone (GCTB) is an expansile osteolytic tumour which contains numerous osteoclast-like giant cells. GCTB frequently recurs and can produce metastatic lesions in the lungs. Bisphosphonates are anti-resorptive drugs which act mainly on osteoclasts.
In this study, we have examined clinical and radiological outcomes of treatment with aminobisphosphonates on 25 cases of aggressive primary, recurrent and metastatic GCTB derived from four European centres. We also analysed in vitro the inhibitory effect of zoledronic acid on osteoclasts isolated from GCTBs.
Treatment protocols differed with several different aminobisphosphonates being employed, but stabilisation of disease was achieved in most of these cases which were refractory to conventional treatment. Most inoperable sacral/pelvic tumours did not increase in size and no further recurrence was seen in GCTBs that had repeatedly recurred in bone and soft tissues. Lung metastases did not increase in size or number following treatment. Zoledronic acid markedly inhibited lacunar resorption by GCTB-derived osteoclasts in vitro.
Our findings suggest that bisphosphonates may be useful in controlling disease progression in GCTB and that these agents directly inhibit GCTB - derived osteoclast resorption. These studies highlight the need for the establishment of standardised protocols to assess the efficacy of bisphosphonate treatment of GCTB.
PMCID: PMC2940802  PMID: 20799989
18.  Aneurysmal Bone Cysts: Do Simple Treatments Work? 
Primary aneurysmal bone cysts (ABCs) are benign, expansile bone lesions commonly treated with aggressive curettage with or without adjuvants such as cryotherapy, methacrylate cement, or phenol. It has been reported that occasionally these lesions heal spontaneously or after a pathologic fracture, and we observed that some ABCs treated at our center healed after biopsy alone. Because of this, we introduced a novel biopsy technique we call “curopsy,” which is a percutaneous limited curettage at the time of biopsy, obtaining the lining membrane from various quadrants of the cyst leading to consolidation (curopsy = biopsy with intention to cure).
We asked whether (1) a curopsy results in comparable likelihood of healing of the ABC compared with more aggressive approaches involving curettage, (2) the two approaches differ in terms of the likelihood of recurrence after treatment, and (3) the two approaches differ in terms of complications after surgery.
Between January 1, 1999 and June 30, 2012, 221 patients with a diagnosis of primary ABC were registered in our oncology database. Patients presenting with a pathologic fracture and those seeking a second opinion were excluded. One hundred ninety patients were included in the study. One hundred two (54%) were treated with curopsy and 88 (46%) were treated with curettage after a core needle biopsy. Complete followups were available for 88% (90 of 102) and 93% (80 of 88) of patients in those groups, respectively. During that period, a curopsy was performed for all patients with benign bone lesions with imaging suggestive of classic primary ABCs and for whom the core needle biopsy simply showed blood with no solid component. Curettage after a core needle biopsy was reserved for histologically confirmed primary ABCs, lesions with impending fractures, large lesions, if the ABC was thought to be a secondary disorder, and patients for whom the curopsy failed. All patients were followed up until consolidation of the lesion (mean, 9.6 weeks, range, 3–25 weeks, 95% CI, 8.32–10.9 for curopsy; mean, 11.4 weeks, range, 8–32 weeks, 95% CI, 10.6–12.3 for curettage). The median followup for all patients was 14 months (range, 6–36 months).
Of the 102 patients who had curopsy and observation, 83 (81%) required no additional treatment and the lesion resolved. Of the 88 patients who underwent curettage (with or without adjuvant therapy) after core needle biopsy, the success rate was 90% (79 of 88). Local recurrences in both groups (curopsy or curettage) were treated successfully with additional curettage in all but one case. Curopsy in comparison to curettage provided a mean shorter healing time (9.6 versus 11.4, p = 0.01) but there was a higher local recurrence and need for additional intervention rate (18.6% versus 10.2%, p = 0.04). There were no differences in the complications between the treatment groups.
A curopsy is a novel biopsy technique that was successful in resolving ABCs in 81% of the patients in our study. Curopsy, as a biopsy technique, for ABCs needs consideration as it potentially minimizes the number of patients needing a second procedure (a core needle biopsy being the first) as is the current practice. Furthermore, it does not disadvantage the patient or surgeon should additional intervention be needed in the form of curettage with or without adjuvants.
Level of Evidence
Level III, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence.
PMCID: PMC4016447  PMID: 24532435
19.  Treatment for giant cell tumor of the spine metastasizing to the lung: A report of two cases and a literature review 
Oncology Letters  2014;9(3):1321-1326.
Giant cell tumors of the bone (GCTB) account for 5% of all primary skeletal tumors. Although the tumors are normally benign, recurrence and metastasis of GCTB does occur. The most usual sites of a primary GCTB lesion are the distal femur and proximal tibia, and ~3% of these metastasize to the lung. Primary GCTB lesions in the spine are rare, and there have been few cases reporting the pulmonary metastasis of GCTB in the spine. The present study reports two cases of thoracic and sacral spinal GCTB lesions with pulmonary metastasis. One of the patients was a 45-year-old male who presented to hospital with gradually worsening pain in the left buttock during the last two years and was diagnosed with GCTB of the sacrum. The other patient was a 30-year-old female who complained of persistent back pain for a year and was also diagnosed with GCTB of the sacrum. Arterial embolization was performed prior to surgery and computer navigation was used during the surgery, resulting in the two patients achieving en bloc resection of their respective tumors, with satisfactory rehabilitation to follow.
PMCID: PMC4315077  PMID: 25663906
giant cell tumor of the bone; spine; pulmonary metastasis
20.  Multicentric giant cell tumor of the fourth and fifth metacarpals with lung metastases 
Hand (New York, N.Y.)  2013;9(3):389-392.
Giant cell tumors of bone (GCTB) are generally benign neoplasms, but recently, some authors consider them to be low-grade malignant neoplasms because they have a relatively high rate of recurrence and at least some potential for metastases. The majority of GCTB are unifocal, and less than 1 % are multicentric. We report a rare case of a multicentric GCTB arising simultaneously in the non-dominant fourth and fifth metacarpals of a 25-year-old female. The patient underwent ray amputation of the two involved digits, and the surgical margins were histologically negative for tumor. The tumor had the classic histologic appearance of a benign GCTB. A year after the amputation, the patient developed pulmonary metastasis which was treated with pulmonary lobe resection. She is currently over 2.5 years postsurgical treatment of the primary lesion with no evidence of local recurrence or distant metastasis.
PMCID: PMC4152433  PMID: 25191173
Giant cell; Multicentric; Metacarpal; Tumor
21.  Ethanol as a Local Adjuvant for Giant Cell Tumor of Bone 
Giant cell tumor is an aggressive benign neoplasm of bone. A number of adjuvant agents have been used to supplement intralesional curettage to reduce the otherwise high local recurrence rate. High concentration ethanol is more readily available and less toxic to use than some common alternatives. No report on its use in a group of patients with giant cell tumor is available. Records were retrospectively reviewed for all giant cell tumors treated by intralesional curettage and high concentration ethanol irrigation as the only chemical adjuvant. Twenty-five primary excisional curettages and 12 repeat curettages for giant cell tumors of bone were performed in 31 patients. Patients were followed for a mean of three years and 10 months. There were five recurrences after primary excision procedures, and three after repeat excisions. Only use of a high-speed burr and lower Campanacci staging correlated with reduced recurrence rate, and these were not statistically significant. Most defects were filled with allograft or calcium sulfate. In the 11 patients treated primarily with curettage using a high-speed burr and adjuvant ethanol with minimum two-year follow-up, only one stage 3 lesion in a distal radius recurred. Multiple washes with high concentration ethanol, when used in conjunction with aggressive curettage including high-speed burring, is an effective and safe adjuvant. The necessity of any chemical adjuvant after appropriately aggressive curettage and burring can only be definitively demonstrated with a prospective, randomized, multi-center trial. Until such evidence becomes available, the use of adjuvant ethanol offers a compromise between higher toxicity adjuvants and no chemical adjuvant at all.
PMCID: PMC1888590  PMID: 16789453
22.  Similar Local Control between Phenol- and Ethanol-treated Giant Cell Tumors of Bone 
Giant cell tumors (GCTs) of bone often are treated with curettage, adjuvant therapy, and cementation. Phenol is a commonly used adjuvant associated with local control rates ranging from 9% to 25%. However, it is corrosive to the eyes, skin, and respiratory tract. Ethanol is readily available and does not cause chemical burns on contact, but it is unclear whether ethanol can achieve similar local control rates as phenol for treating GCTs.
We evaluated (1) the recurrence rate and recurrence-free Kaplan-Meier survival function, (2) Musculoskeletal Tumor Society (MSTS) functional score (1993 version), and (3) complications of two groups of patients with GCTs treated with extensive curettage, local adjuvant therapy with phenol or ethanol, and cement reconstruction, to determine if ethanol was a reasonable alternative to phenol.
Patients and Methods
We retrospectively reviewed all 26 patients with GCTs in the long bones of extremities treated with curettage, high-speed burring, phenolization, and cementation between May 1995 and November 2001, and 35 patients treated with the same protocol, except phenol was replaced with 95% ethanol, between November 2001 and November 2007. The recurrence rates, Kaplan-Meier recurrence-free survival curves, and MSTS functional scores of these two treatment groups were compared with Fisher’s exact test, Tarone-Ware test, and Mann-Whitney U test, respectively. The minimum followup was 36 months (mean, 58 months; range, 36–156 months).
Local recurrence rates were similar in the two groups: 11% in the ethanol group and 12% in the phenol group. The survival curves (using local recurrence as an endpoint) of the two groups were similar. The mean MSTS functional score was 27.3 (91%) for the ethanol group and 26.9 (90%) for the phenol group.
Ethanol is a reasonable alternative to phenol when adjuvant therapy is considered in the treatment of GCTs of long bones.
Level of Evidence
Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC3183197  PMID: 21732023
23.  Local control of long bone giant cell tumour using curettage, burring and bone grafting without adjuvant therapy 
International Orthopaedics  2006;30(6):495-498.
Giant cell tumour (GCT) is a benign, but aggressive, primary tumour of the bone. The recurrence rate after surgical treatment has been reported to be as high as 50%. Many surgical techniques have been employed in the treatment of this tumour. More aggressive interventions, such as en bloc resection and bulk allograft or prosthetic reconstruction, are generally understood to be associated with lower rates of local recurrence. However, because of lessened morbidity, intralesional techniques have come to be favoured for this condition. In addition to curettage, various adjuvant procedures and packing materials have been advocated in order to control and reconstruct long bone defects secondary to this neoplasm. We report our experience with 40 long bone GCT patients treated with curettage, burring, bone grafting and no adjuvants between 1997 and 2002. There was a local recurrence rate of 32.5%, with most recurrences noted within the first 30 months after surgery. Minor complications were found in 18% of patients. The risk of local recurrence in this study is acceptable (within the range that has been historically reported for curettage and bone grafting). In cases where more resources are available, the addition of adjuvant therapies, as noted in the recent literature, may be beneficial. The results of this study should be considered when designing multicenteric studies in the future.
PMCID: PMC3172751  PMID: 16896875
24.  Curettage and Cryosurgery for Low-grade Cartilage Tumors Is Associated with Low Recurrence and High Function 
Chondrosarcomas of bone traditionally have been treated by wide or radical excision, procedures that may result in considerable lifelong disability. Grade 1 chondrosarcomas have little or no metastatic potential and are often difficult to distinguish from painful benign enchondromas. Curettage with adjuvant cryosurgery has been proposed as an alternative therapy for Grade 1 chondrosarcomas given the generally better function after the procedure. However, because it is an intralesional procedure, curettage and cryosurgery may be associated with higher rates of recurrence.
We asked whether Grade 1 chondrosarcomas and enchondromas of uncertain malignant potential treated by curettage and cryosurgery are associated with low recurrence rates and high functional scores.
Patients and Methods
We retrospectively reviewed the records of 46 patients with Grade 1 chondrosarcomas and enchondromas of uncertain malignant potential treated by curettage and cryosurgery. Forty-one patients had tumors of the long bones. Patients were followed a minimum of 18 months (average, 47.2. months; range, 18–134 months) for evidence of recurrence and for assessment of Musculoskeletal Tumor Society (MSTS) functional score.
Two of the 46 patients had recurrences in the original tumor site (4.3% recurrence rate), which subsequently were removed by wide excision, and both patients were confirmed to be disease-free 36 and 30 months, respectively, after the second surgery. The mean MSTS score was 27.2 of 30 points (median, 29 points).
Our observations show curettage with cryosurgery is associated with low recurrence of Grade 1 chondrosarcoma and high functional scores. Curettage with cryosurgery is a reasonable alternative to wide or radical excision as the treatment for Grade 1 chondrosarcomas, and allows for more radical surgery in the event of local recurrence.
Level of Evidence
Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC3049634  PMID: 20574801
25.  Conservative Treatment of Campanacci Grade III Proximal Humerus Giant Cell Tumors 
Management of large giant cell tumors of the proximal humerus is controversial because wide resection with reconstruction results in a poor functional outcome for most patients. We retrospectively reviewed the cases of six patients with Campanacci Grade III giant cell tumors of the proximal humerus to determine the feasibility of avoiding en bloc resections for large giant cell tumors in this location. We evacuated the tumor through curettage and then used burring (unless the remaining cavity was thinned and at risk for fracture) and phenolization, followed by packing of the defect with allograft cancellous bone. The mean age of the patients at surgery was 30 years, and the minimum followup was 2.5 years (mean, 5.6 years; range, 2.5–9.7 years). One of the six patients had local recurrence 1.2 years postoperatively and was treated with repeat intralesional surgery with no additional recurrence 5 years later. No other patient required additional treatment, had pulmonary metastases develop, or had progression to osteoarthritis. The mean Musculoskeletal Tumor Society and Toronto Extremity Salvage Score functional scores at last followup were 26 of 30 (range, 21–30) and 95% (range, 90%–100%), respectively. These functional scores are higher than reported scores for patients with segmental resection and reconstruction of the proximal humerus.
Level of Evidence: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC2664411  PMID: 18987923

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