Giant Cell Tumor Patients Research Articles

Pathomorphological & Radiological Changes Following Denosumab Treatment In Giant cell tumours

Introduction:- The introduction of denosumab has significantly impacted the treatment approach for giant cell tumors (GCTs) of bone, a locally aggressive osteolytic neoplasm. This study aimed to comprehensively investigate the pathomorphological and radiological changes observed in GCT patients following neoadjuvant denosumab therapy. Material methods: - A retrospective analysis of 12 cases was conducted, encompassing primary and recurrent GCT cases treated with denosumab. Clinical, radiological, and histopathological features were thoroughly examined. All cases displayed Campanacci grade 3 lesions with ambiguous borders. Results: - Neoadjuvant denosumab treatment led to distinct clinical benefits, including reduced intraoperative bleeding and increased bone density, facilitating surgical procedures. Histopathologically, denosumab-treated cases exhibited enhanced cellularity, prominent fibroblastic proliferation, spindle cell arrangement, osteoid formation, and fibro-osseous components. The number of osteoclast-type giant cells significantly diminished, sometimes approaching absence. Immunohistochemical analysis using P63 corroborated the diagnosis. Radiologically, denosumab-induced changes included marked osteosclerosis, sclerotic rim formation, and increased intralesional osteosclerosis. Conclusion: - These findings emphasize the significance of recognizing the diverse morphological and radiological alterations in denosumab-treated GCTs.

Interferons as Neoadjuvant Chemotherapy for Giant Cell Tumor: A Hospital-Based Prospective Pilot Study

Abstract Introduction Neoadjuvant chemotherapy is now considered an effective way to treat Campanacci grade 2 and 3 giant cell tumors (GCTs). Assessment of these drugs is essential clinically, radiologically, and pathologically. This study analyzes the early results of angiogenesis inhibitors (interferons) in the aggressive GCT of bone. Methodology A prospective pilot study was conducted from January 2021 to July 2022 including eight biopsy-proven GCT patients subjected to interferon therapy. Radiological assessment was done with changes on plain radiograph, computerized tomography scan, and magnetic resonance imaging. Histopathological examination was done by changes in the biopsy and resected segment. Results Out of the eight patients included in the study, 26% (n = 3) were males and 62% (n = 5) were females, with mean age of the patients being 24.6 ± 8.48 years (range: 22–38). There was significant reduction of the size of swelling (p-value: 0.049), significant reduction in Visual Analog Scale score (p-value: 0.011), significant decrease in swelling size on radiograph (p-value: 0.012), significant marginal sclerosis (p-value: 0.001), significant neocortex formation on radiographs (p-value: 0.001), significant result in and osteoid formation (p-value: 0.001) on histology. Whereas Campanacci grade on plain radiographs, number of viable cells, and number of viable stromal cell were not statistically different in comparison with pretherapy and posttherapy status. Conclusion Interferon therapy in a GCT has potential beneficiary effect in terms of clinical, radiological, and pathological outcomes. It might prove to be an effective alternative to standard neoadjuvant chemotherapy in the management of aggressive GCT of bones. Level of Evidence III.

Histopathological response to denosumab in giant cell tumours of bone - A review of 11 cases.

Giant cell tumor (GCT) of the bone is a locally aggressive primary bone tumor, that can rarely metastasize. Arising mostly in epiphysis of the long bones in young adults, the tumor is composed of mononuclear cells that are admixed with osteoclastic giant cells(OLGCs), which express RANK ligand and RANK respectively. Denosumab a monoclonal antibody against RANK ligand has been shown to reduce the tumor by causing bone lysis by inhibiting RANKL. Histological changes in 11 patients of GCT who were treated with denosumab are presented here. Clinical records and slides of 11 patients of GCT who had been administered neoadjuvant denosumab were included in the study. Evaluation of pre and post therapy GCT specimens was performed by two pathologists (RK and VM). There were 4 males and 7 females. Their mean age was 30 years. All the patients received 120 mg denosumab subcutaneously every week with additional 120 mg on days 8 and 15 of therapy. The histological slides were reviewed and following points noted: 1) degree of ossification,2) fibrosis,3) loss of osteoclastic giant cells,4) proliferation of mononuclear cells,5) atypia,6) Permeation of osteoid by malignant cells. Out of 11 cases, 2 cases did not show any significant histological improvement. 7 cases showed reduction in giant cells, increased fibrosis, enhanced mononuclear cell proliferation and ossification consistent with a pathological response. Atypia and osteoid permeation were noted in 2 cases which showed transformation to osteosarcoma. Denosumab treated giant cell tumor show dramatic histological changes. The post therapy lesions may bear no resemblance to pretherapy lesion. There may be complete resolution or may be confused with benign or malignant lesions Rarely they may show sarcomatous transformation. It is imperative that the pathologist is aware of these changes to prevent diagnostic pitfalls as it poses therapeutic and prognostic implications.

Role of Denosumab in the Management of Giant Cell Tumor, a Cross Sectional Study

ABSTRACT Background: Giant cell tumor (GCT) of bone is a benign lesion which is characterized by presence of multinucleated osteoclasts type giant cells. Nuclear factor kappa B (RANKL) serves as the trigger factor for osteoclasts cells formation. Although surgery is the primary treatment for GCT of bone but recurrence remains the concern. Therefore, the development of denosumab, a monoclonal antibody for treating GCT for both primary and recurrent disease cases. The present study aims to show the role of denosumab along with surgery when given as neo-adjuvant drug to patients of GCT for their treatment. Methodology: A total of 23 patients diagnosed with GCT were included in this study from January 2016–December 2019 and all of these patients had received neo adjuvant denosumab dose of 120 mg SC on day 0, 15, 30 & 45. All patients were treated at the section of Orthopedics, department of surgery, Aga Khan University hospital, Karachi. Other benign lesions were excluded from the study. Results: Out of 23 patients we had 12 (52.2%) males and 11 (47.8%) females. The mean age of our patients was 34±13.8 years and mean follow up duration of all patients was 20.5 ± 10.7 months. There were 15 (65.2%) primary cases of GCT while 8 (34.8%) were recurrent cases. In 8 (34.8%) of the cases primary site of lesion was distal femur followed by 7(30.4%) proximal tibia cases and 3(13%) distal radius cases. In surgical procedure 20 (87%) patients underwent wide margin excision and only 3 (13%) had intralesional curettage. Reconstruction was performed in 21 patients which consist of bone grafting in 9 patients and mega prosthesis insertion in 12 patients. Only two patients had no reconstruction. On final histopathology, there was no residual GCT and we observed no denosumab induced adverse effects. Post-operative complications included wound infection and peri prosthetic infection in 3 patients. On follow-up we had 4(17.4%) cases of recurrence that were offered revision surgery while 19 (82.6%) were disease free. Conclusion: Denosumab has shown successful results in treating patients with GCT along with surgical intervention and it can be a best option for treating recurrent disease as well. Highlights Research registration no: researchregistry4695

Treatment of giant cell tumor of bone using bone grafting and cementation with versus without gel foam

ABSTRACT Background Giant cell tumor (GCT) of bone is a benign locally aggressive tumor that constitutes 20% of the body's benign bone tumors. Most of the GCTs exhibit a typical epiphyseal location that shows a tendency for significant bone destruction and local recurrence. We aimed to assess the functional and oncological outcomes of GCT patients treated with bone grafting and cementation with or without gel foam. Materials and methods This prospective study included 40 patients presented at El Hadara University Hospital with GCT of bone around the knee from January 2017 to January 2022 treated by bone graft and cementation. Twenty cases were treated with gel foam (Group I) and 20 cases were treated without gel foam (Group II) through random allocation without selection. Recurrence was assessed as progressive lysis of 5 mm at the bone cement interface. Functional outcomes were assessed using the musculoskeletal tumor society score (MSTS) after a period of minimum 30 months. Results In Group I, 18 patients (90%) had excellent results (range 24 and 30) according to MSTS and two patients (10%) had good results (range 18 and 23), while in Group II, 16 patients (80%) had excellent results and four patients (20%) had good results. No patients were graded as having fair or poor results. Twenty patients (100%) had satisfactory results, and no patients (0%) had unsatisfactory results. The overall recurrence rate was about 15%. Conclusion Reconstruction of GCT of bone with sandwich technique offers good option as joint preserving surgery. Most of the patients get benefit in terms of better quality of life and good function regardless of age and gender. Subchondral bone grafting reduces the effect of heat on articular cartilage, but longer follow-up is required. There is no benefit of gel foam addition in terms of function or oncological outcome.

Wide excision and reconstruction with free vascularized fibula for aggressive giant cell tumor of distal 3rd tibia

Giant cell tumor (GCT) at distal end of tibia is relatively a rare site of occurrence. We presented our experience with extensive excision and reconstruction for GCT of distal tibia using a free vascular double strut/single strut fibula graft. The present case series was conducted on six patients of GCT at lower end of tibia who were treated with extensive excision and reconstruction either in index (n=4) or recurrence (n=2) settings. Four patients were male and 2 were female. The mean age was 26.5 years. The average length of bone defect after tumor excision was 7.4 cm. The range of movement at ankle joint up to 70% of normal opposite side achieved in 2 cases and arthrodesis of ankle joint done in rest 4 cases (2 recurrent and 2 index cases). In GCT treatment, in spite of reconstruction difficulty for bony defect of lower end tibia due to its weight bearing property, vascularized free fibula graft has advantages like allows wide excision of tumor, single stage procedure, early weight bearing capacity in young patients and no bone resorption but bone thickening.

Radiologic and clinical changes after denosumab treatment for giant cell tumors of the mobile spine: a quantitative study

ObjectivesTo analyze the radiologic and clinical changes after denosumab treatment in patients with giant cell tumors (GCTs) in the mobile spine.MethodsClinical data and images by computed tomography and magnetic resonance imaging at a single center were retrospectively reviewed before and after denosumab treatment.ResultsPre- and post-treatment data from 24 patients were evaluated. On imaging, marginal ossification and/or bone formation was observed in 22 patients (91.7%). The median maximum diameter of the GCT reduced from 52.5 to 48.2 mm (p < 0.001), and the mean proportion of tumor to spinal canal area decreased from 36.8 to 18.5% (p < 0.001). Out of six patients with compression, three patients (50%) showed no compression after treatment. The signal intensity (SI) ratio between the solid part of the tumor and the normal spinal cord on T2-weighted MR images was 0.77 ± 0.22 and decreased to 0.58 ± 0.22 (p = 0.001). On clinical symptoms, the mean visual analog scale scores were reduced from 5.3 to 2.0 (p < 0.001) and the Karnofsky Performance Scale scores increased from a median of 65 to 80 (p < 0.001). Post-treatment, performance scores improved in eight patients (33.3%) (p = 0.003), and the neurological function of four patients improved according to Frankel grade (p = 0.046).ConclusionsBone formation, tumor reduction, regression of epidural lesion and the decrease in SI ratio on T2-weighted image should be considered as the effectiveness of denosumab in the treatment of spinal GCT. In clinical application, denosumab can relieve pain, improve neurological function, and improve the quality of life of spinal GCT patients.

Mechanisms of Cytotoxicity of Chemical Agents to Giant Cell Tumors: An In Vitro Study.

Background Various chemical agents have been used as an adjuvant treatment for giant cell tumor (GCT). However, the comparative effect of these chemicals remains unclear. Methods Multinucleated and spindle cells from cultured GCT patients, characterized by Nanog and Oct4 expression with RT-PCR, were directly administered, in vitro, with concentrations of 1%, 3%, and 5% of H2O2 and 75%, 85%, and 95% of ethanol for 10 minutes and concentrations of 0.003%, 0.005%, 0.01%, 0.03%, 0.1%, and 0.3% of H2O2 for 5 minutes and were incubated for 24 hours. Cell morphology, cell viability, and flow cytometry after various concentrations of H2O2 and ethanol exposure were assessed. Results H2O2 in all concentrations caused loss of cell viability. The number of viable cells after H2O2 exposure was related to the concentration-dependent effect. The initial viable spindle-shaped cell, multinucleated giant cell, and round-epithelioid cell had morphological changes into fragmented nonviable cells after exposure to H2O2. Flow cytometry using Annexin V showed cell death due to necrosis, with the highest concentration amounting to 0.3%. Conclusion Administering local chemical adjuvants of H2O2 in vitro caused loss of viable GCT cells. The number of viable cells after H2O2 exposure was related to the concentration-dependent effect, whereas reducing concentration of H2O2 may cause loss of viability and morphology of cultured GCT cells with the apoptotic mechanism.

Plasma metabolite profiling reveals potential biomarkers of giant cell tumor of bone by using NMR-based metabolic profiles: A cross-sectional study.

Giant cell tumor (GCT) of bone is a locally aggressive bone tumor, which accounts for 4% to 5% of all primary bone tumors. At present, the early diagnosis and postoperative recurrence monitoring are still more difficult due to the lack of effective biomarkers in GCT. As an effective tool, metabolomics has played an essential role in the biomarkers research of many tumors. However, there has been no related study of the metabolomics of GCT up to now. The purpose of this study was to identify several key metabolites as potential biomarkers for GCT by using nuclear magnetic resonance (NMR)-based metabolic profiles.Patients with GCT in our hospital were recruited in this study and their plasma was collected as the research sample, and plasma collected from healthy subjects was considered as the control. NMR was then utilized to detect all samples. Furthermore, based on correlation coefficients, variable importance for the projection values and P values of metabolites obtained from multidimensional statistical analysis, the most critical metabolites were selected as potential biomarkers of GCT. Finally, relevant metabolic pathways involved in these potential biomarkers were determined by database retrieval, based on which the metabolic pathways were plotted.Finally, 28 GCT patients and 26 healthy volunteers agreed to participate in the study. In the multidimensional statistical analysis, all results showed that there was obvious difference between the GCT group and the control group. Ultimately, 18 metabolites with significant differences met the selection condition, which were identified as potential biomarkers. Through Kyoto Encyclopedia of Genes and Genomes (KEGG) and Human Metabolome Database (HMD) database searching and literature review, these metabolites were found to be mainly correlated with glucose metabolism, fat metabolism, amino acid metabolism, and intestinal microbial metabolism. These metabolic disorders might, in turn, reflect important pathological processes such as proliferation and migration of tumor cells and immune escape in GCT.Our work showed that these potential biomarkers identified appeared to have early diagnostic and relapse monitoring values for GCT, which deserve to be further investigated. In addition, it also suggested that metabolomics profiling approach is a promising screening tool for the diagnosis and relapse monitoring of GCT patients.

Long-term results of the Global Modular Replacement System tumor prosthesis for reconstruction after limb-sparing bone resections in orthopedic oncologic conditions: Results from a national cohort.

We investigated implant revision, implant failure, and amputation risk after limb-sparing bone tumor surgery using the Global Modular Replacement System (GMRS) tumor prosthesis in patients suffering from bone sarcomas (BS), giant cell tumors (GCT), or metastatic bone disease (MBD). A retrospective study of a nationwide consecutive cohort (n = 119, 47 [12-81] years, M/F = 65/54) having limb-sparing surgery and reconstruction using the GMRS tumor prosthesis due to bone tumors (BS/GCT/MBD = 70/8/41) from 2005 to 2013. Anatomical locations were as followed: distal femur (n = 49), proximal femur (n = 41), proximal tibia (n = 26), or total femur (n = 3). Kaplan-Meier survival analysis and competing risk analysis with death as a competing risk were used for statistical analysis. For BS and GCT patients, 5-year patient survival was 72% (95% confidence interval [CI]: 59-85%) and for MBD 33% (95% CI: 19-48%). Thirty-two patients underwent revision surgery (5-year revision incidence 14%; 95% CI: 8-21%). Twelve patients had revision of bone-anchored parts (implant failure) with a 5-year revision incidence 6% (95% CI: 2-10%). Ten amputations were performed due to local relapse (n = 9) or recurrent infections (n = 1) with a 5-year incidence of amputation: 8% (95% CI: 3-13%). We identified a low risk of revision and amputation when using the GMRS tumor prosthesis for limb-sparing bone tumor.

Circulating Candidate Biomarkers in Giant Cell Tumors of Bone.

Approximately 5% of giant cell tumors (GCT) of bone develop pulmonary metastases. Although many biomarkers have been proposed, identification of circulating low abundance molecules may be useful to predict malignant progression. The hydrogel nanoparticle technique followed by MS was used to detect low molecular weight serum proteins or protein fragments in serum of 20 GCT patients with different clinical course and in ten healthy sera used as control. The most representative low-abundant de novo or differentially abundant proteins were submitted to String database that recognized interconnected activated pathways including protein activation cascade, wound healing, cell-substrate adhesion, and response to stress. Statistics were performed for identification of candidate prognostic factors. Proteome cluster analysis separated metastasis-free from metastatic GCT patients in two well-defined groups where serum levels of signaling transduction mediators and regulators of kinase activity presented a high discriminatory power. Increased expression of proteins STAT5B, GRB2, and OXSR1 was related to a higher probability of metastasis. Multivariate analysis demonstrated that tumor grade and STAT5B were independent prognostic factors. By using a noninvasive technique, we identified differentially abundant serum candidate biomarkers, also providing prognostic information in patients with GCT of bone.

Denosumab does not decrease the risk of lung metastases from bone giant cell tumour.

There are conflicting reports on the effect of denosumab on lung metastases in patients with giant cell tumor (GCT) of bone. To address these reports, we performed this study to determine if denosumab prevents lung metastasis and to evaluate univariate and multivariate predictors for lung metastases in these patients. We retrospectively studied 381 GCT patients with surgery alone and 30 GCT patients with surgery and denosumab administration. The median follow-up was 85.2months (IQR, 54.2-124.4months). We evaluated lung metastases and local recurrences, univariate and multivariate predictors for lung metastases, response, and adverse events of denosumab administration. The occurrence of lung metastases was similar (surgery alone 4.7%, 18 patients; denosumab administration 3.3%, 1 patient); however, the occurrence of local recurrences was significantly higher in the patients with denosumab administration. Denosumab administration was not an important predictor for lung metastases; Campanacci stage and type of surgery were the only univariate predictors for lung metastases, and type of surgery and local recurrence were the only multivariate predictors for lung metastases. Histology showed viable tumour in all tumor specimens of the patients with denosumab administration. Denosumab does not decrease the risk of lung metastases in patients with bone GCT; the only important predictors for lung metastases in these patients are type of surgery and local recurrence. However, because the number of patients with lung metastases was small for a multivariate analysis, the possibility of denosumab's effect could not be completely eliminated.

Nomograms for prognostic factors of spinal giant cell tumor combining traditional clinical characteristics with inflammatory biomarkers after gross total resection.

Giant cell tumor (GCT) of bone is a common primary bone tumor, which exhibits local aggressiveness and recurrent potential, especially for the spinal lesion. Increasing evidence indicates that inflammation plays a vital role in tumorigenesis and progression. The prognostic value of inflammatory biomarkers in GCT has not been established. A retrospective analysis was conducted in patients with spinal GCT in Changzheng Hospital Orthopedic Oncological Center (CHOOC) between January 2005 and October 2015 and 129 patients were identified eligible. Traditional clinical parameters and inflammatory indexes such as Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and albumin/globulin ratio (AGR) were concluded and analyzed. Kaplan-Meier analysis was used to calculate the disease-free survival (DFS). Cox regression analysis was performed to assess the prognostic factors. Nomograms were established to predict DFS quantitatively for the first time, and Harrell’s concordance index (c-index) was adopted to evaluate prediction accuracy. As results, the DFS was 78.3% in the cohort. Patients were stratified into 2 groups by NLR (≤ 2.70 and > 2.70), PLR (≤ 215.80 and > 215.80), LMR (≤ 2.80 and >2.80) and AGR (< 1.50 and ≥ 1.50). Patients with NLR > 2.70, PLR > 215.80, LMR ≤ 2.80 and AGR < 1.50 were significantly associated with decreased DFS (p < 0.05). Multivariate analysis indicated that treatment history, tumor length, bisphosphonate treatment, NLR and PLR were independent factors of DFS (p < 0.05, respectively). In addition, nomogram on DFS was established according to all significant factors, and c-index was 0.728 (95% CI: 0.710-0.743). Nomograms based on DFS can be recommended as practical models to evaluate prognosis for spinal GCT patients.

Recurrence Factors in Giant Cell Tumors of the Spine.

Background:Giant cell tumors (GCTs) are benign, locally aggressive tumors. We examined the rate of local recurrence of spinal GCTs and sought to identify recurrence factors in patients who underwent surgery.Methods:Between 1995 and 2014, 94 mobile spine GCT patients were treated at our hospital, comprising 43 male and 51 female patients with an average age of 33.4 years. Piecemeal intralesional spondylectomy and total en bloc spondylectomy (TES) were performed. Radiotherapy was suggested for recurrent or residual GCT cases. Since denosumab was not available before 2014 in our country, only interferon and/or zoledronic acid was suggested.Results:Of the 94 patients, four underwent conservative treatment and 90 underwent operations. Seventy-five patients (79.8%) were followed up for a minimum of 24 months or until death. The median follow-up duration was 75.3 months. The overall recurrence rate was 37.3%. Ten patients (13.3%) died before the last follow-up (median: 18.5 months). Two patients (2.6%) developed osteogenic sarcoma. The local recurrence rate was 80.0% (24/30) in patients who underwent intralesional curettage, 8.8% (3/34) in patients who underwent extracapsular piecemeal spondylectomy, and 0 (0/9) in patients who underwent TES. The risk factors for local recurrence were lesions located in the cervical spine (P = 0.049), intralesional curettage (P < 0.001), repeated surgeries (P = 0.014), and malignancy (P < 0.001). Malignant transformation was a significant risk factor for death (P < 0.001).Conclusions:Cervical spinal tumors, curettage, and nonintact tumors were risk factors for local recurrence. Intralesional curettage and malignancy were the most important significant factors for local recurrence and death, respectively.

Giant cell tumor of distal radius treated with ulnar translocation and wrist arthrodesis.

The aim is to analyze the functional outcomes of patients of giant cell tumor (GCT) of distal radius treated with ulnar translocation and wrist arthrodesis. Study included 25 patients of aggressive GCT of distal radius, resected and reconstructed using ulnar translocation and wrist arthrodesis. The ulna-carpal radius fixation was performed with plate and screws. The patients were followed to bony union and minimum follow-up was 1 year. Twenty-two patients were of Campanacci grade 3 and three patients were of Campanacci grade2. The mean follow-up was of 23 months (12-36). All patients had an excellent range of pronation and supination. The mean Musculoskeletal Tumor Society score was 24 (range 22-28). Grip strength of affected hand compared to the contra lateral hand was found good in 17 cases and average in 7 cases. The mean bone union time at ulna to radius junction was at 6.5 (5-8) months and ulna to carpal junction at 4.5 (4-6) months. The complications were surgical site infection (one case), recurrence (one case) and failure of union (one case), and ulna graft fracture with implant failure in (two cases). Reconstruction of distal end of radius using ulnar translocation and wrist arthrodesis provides excellent functional outcomes with preservation of rotational movement of forearm and hand function. Reconstruction of the distal radius by ulnar translocation without complete detachment from surrounding soft tissues functions like vascularized graft without use of microvascular techniques.

Correlation between p63 expression and clinical behavior of giant-cell tumor of bone

Giant-cell tumor (GCT) is a type of bone tumor that is usually benign. In this study, we investigate the clinicopathological features of GCT and identify unreported characteristics of such disease in Iranian patients. In this study, 50 GCT patients had been treated at a referral orthopedic hospital from March 2003 through March 2013. The patients’ sex, age, location of tumor, presenting symptoms, treatment methods, and recurrence rate were determined. To confirm the reliability of the initial diagnosis, hematoxylin and eosin (H-E) staining and P63 immunostaining were used. In this sample, 52 % of patients were male and 48 % were female. Among these patients, the most common symptom was pain. The most frequent surgical technique used for this group was the curettage, graft, and en bloc method. The lowest rate of tumor recurrence was observed in this technique. With the p63 immunostaining method, 27 cases were weakly positive and 14 cases were positive, while 9 cases were highly positive with episodes of recurrence. Of all body parts, GCT most commonly affects the knee. In our patients, the recurrence rate was 16 %, and all episodes of recurrence were observed in highly positive p63 patients. In summary, p63 could be a useful biomarker for the prognostication and assessment of GCT invasion.

Clinical characteristics and evolution of giant cell tumor occurring in Paget's disease of bone.

Patients with Paget's bone disease (PDB) have an increased risk of developing giant cell tumor (GCT). This study was performed to evaluate the clinical characteristics and evolution of GCT complicating PDB and to compare these clinical characteristics to those observed in two large PDB cohorts, the PDB Italian Registry and the United Kingdom's Multi-Centre Randomised Controlled Trial of Symptomatic Versus Intensive Bisphosphonate Therapy for Paget's Disease (PRISM) study. A systematic literature review identified 117 cases of PDB complicated by GCT (PDB-GCT), which involved the skeletal sites affected by PDB (110 patients) or the extraskeletal tissues adjacent to affected bones (7 patients). In contrast to what previously reported for GCT patients without GCT patients (83.2%) were white and one-fourth of them (24.8%) had multifocal GCTs. Compared to PDB patients without GCT, PDB-GCT patients showed a higher male/female ratio (2.1 versus 1.2) and more severe disease (age at PDB onset 52.1 ± 12.1 versus 63.3 ± 10.6 years; number of affected sites 6.1 ± 2.9 versus 2.34 ± 1.6; prevalence of polyostotic PDB 93.3% versus 60.6%). The mortality rate of PDB-GCT patients was higher than those occurring in GCT patients without PDB (about 50% versus 0% to 5% at 5 years) or in PDB patients without GCT (log rank = 29.002). Moreover, up to 98% of PDB-GCT cases had elevated total alkaline phosphatase levels at neoplasm diagnosis, suggestive of active PDB. Importantly, PDB-GCT patients from Southern Italy (45.6% of all GCT patients) showed a higher prevalence of multifocal GCT (51.7%) and of positive familial history for PDB (70.8%) and GCT (65.0%). Finally, indirect evidence suggests a decline in the incidence of GCT in PDB patients. The occurrence of GCT in PDB patients is associated with severe disease and reduced life expectancy of affected patients. The increased prevalence of familial diseases in PDB-GCT patients from Southern Italy suggests a founder effect. The observed changes over time in the incidence of GCT in PDB patients could be related to improved clinical management and/or living conditions of patients.

Systemic Therapy in Patients with Resectable and Unresectable Cases of Giant Cell Tumor: A Systematic Review

Background: Giant cell tumor (GCT) is a common benign tumor of the appendicular and axial skeleton that represents 5% of all primary bone tumors. In recent years, the combination of conventional aggressive curettage with targeted adjuvant anti-osteoclastic agents including bisphosphonates and denosumab have led to lower recurrence rates in patients with GCT in a small number of retrospective case series. Furthermore, efficacy of the same anti-osteoclastic agents has been shown in cases of unresectable GCT of bone, leading to decreased rates of tumor progression and stabilization of disease. This review assesses whether the current literature weakly, moderately, or strongly supports a targeted systemic treatment as the standard of care in patients with GCT. Methods: We conducted a current search of the MEDLINE database for literature pertaining to systemic GCT treatment. Our inclusion criteria were as follows: 1) studies that reported on a series of patients with resectable or unresectable cases of GCT; 2) a subset of patients must have been treated with systemic bisphosphonate or RANK-L inhibitor therapy; 3) each series had a minimum of 10 patients with histopathologically confirmed GCT; 4) each series stated their follow-up period. Results: Overall 6 studies, reporting on a total of 487 patients, were selected for inclusion in this review. For analysis, these 6 retrospective studies were subdivided into series where all GCT patients had resectable tumors (n = 4) and series where patients had a mix of resectable and unresectable tumors (n = 2). The overall recurrence rate of GCT in patients with resectable tumors treated with adjuvant systemic bisphosphonates was 6.7% compared to 48.4% in patients not treated with adjuvant systemic bisphosphonates (p 0.0001). In patients with both resectable and unresectable primary aggressive, recurrent, or metastatic GCT disease, systemic bisphosphonate and denosumab demonstrated good efficacy with decreased rates of disease progression and recurrence. In general the side effects of bisphosphonates were mild while denosumab had a more severe side effect profile. Conclusions: Systemic treatment with bisphosphonates or denosumab in cases of GCT is promising, but there is a lack of high-level evidence with sufficient follow-up supporting their use. We believe the current literature provides moderate support to recommend a short course of adjuvant peri-operative systemic bisphosphonate treatment for patients with resectable primary GCT and moderate support to recommend adjuvant peri-operative (resectable) and non-operative (unresectable) use of denosumab in cases of primary aggressive, recurrent, or metastatic GCT. With either systemic treatment, patients should be well counseled on all potential side effects in addition to alternative treatment, which includes the option of no systemic treatment.

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

BackgroundReports 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.MethodsMedline, 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.ResultsOf 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).ConclusionsLocal 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.

A retrospective analysis of 140 patients with giant cell tumor in the extremity: A multicenter study based on four hospitals in South China

Background: Update reports are rarely available regarding the bone giant cell tumors (GCTs) in the extremity in Chinese people. The aim of this study was to review the epidemiological characteristics of bone GCT in the extremity based on the clinical data from four hospitals in South China. Methods: We searched medical electronic records from January 2001 to December 2011 in four hospitals in South China to identify patients with definite diagnosis of extremity GCT. Epidemiological data including gender, tumor site, age at the time of first diagnosis, local recurrence and pulmonary metastasis were collected and analyzed statistically. Differences between-genders were particularly analyzed regarding first diagnosis age, tumor site, local recurrence and pulmonary metastasis. T-test and Chi-square test were used for continuous and dichotomous variables, respectively. Results: A total of 140 GCT patients (87 males and 53 females) were identified. The gender ratio was 1.64 for a male predominance. GCTs were mostly located around the knee (67 cases). 92 patients were in their 20s to 40s upon first diagnosis. The average age at the time of first diagnosis for all was 30.49 years, 30.76 years for males and 30.06 years for females (P=0.757). GCT recurred locally in 50 patients (26 males and 24 females) with no gender difference (P=0.065). The average interval from first surgery to local recurrence was 21.42 months. Pulmonary metastasis was found in 11 patients (8 males and 3 females) also with no gender difference (P=0.667). The average interval from first diagnosis to metastasis was 36.45 months. Conclusions: Extremity GCT may have a male predominance in Chinese population and mostly occur at 20–40 years of age and around the knee. Follow-ups for GCT patients should be carried on for at least 3 years after primary surgery according to the average intervals for possible local recurrence and pulmonary metastasis.