The Role of Bone Grafting vs. Bone Cement in the Treatment of Giant Cell Tumor of Bone: A Systematic Review and Meta-Analysis on the Risk of Recurrence in 1,454 Patients.

BACKGROUND: Giant cell tumor of bone (GCTB) presents a challenge in management due to its invasive nature and propensity for local recurrence. While either bone grafting (BG) or bone cement (BC) can be utilized to fill defects after intralesional curettage, the optimal treatment remains contested. The purpose of this study was to examine the impact of defect filling with BC compared with BG on recurrence rates in patients with GCTB following intralesional curettage. METHODS: A random-effects model binary outcome meta-analysis was performed utilizing recurrence rate for the BC and BG groups to evaluate the risk ratio (p < 0.05 considered significant). There were 1,454 patients included. RESULTS: Intralesional curettage with BG had a recurrence risk ratio of 1.68 (95% confidence interval [CI], 1.22-2.31, p = 0.001) when compared with BC. The overall rate of recurrence for GCTB after intralesional curettage with BC was 20.05% vs. 29.74% with BG (95% CI, 0.17-0.23 vs. 0.26-0.33, p < 0.001). CONCLUSION: Intralesional curettage with BC for the treatment of GCTB demonstrated lower recurrence rates than intralesional curettage with BG. However, the rates of recurrence remain substantial for both groups, necessitating careful consideration of the benefits and potential pitfalls associated with BC vs. BG when considering salvage options after recurrences. LEVEL OF EVIDENCE: Level III. See Instructions for Authors for a complete description of levels of evidence.

Lymphocyte Infiltration Score and Spatial Characteristics Refined the Prognosis and Denosumab Treatment Responsiveness Indicators for Giant Cell Tumor of Bone.

PURPOSE: The prognostic value of lymphocyte infiltration score (LIS) and its nearest neighbor distance to tumor cells (NNDTC) in giant cell tumor of bone (GCTB) is currently not well established. This study aims to characterize LIS and NNDTC and examine their correlation with denosumab treatment responsiveness, clinicopathologic features, and patient prognosis. METHODS: Using multiplexed quantitative immunofluorescence, LIS was evaluated in 253 tumor specimens, whereas NNDTC was computed using HALO software. Subsequently, we analyzed the association of these parameters with patient outcomes (progression-free survival [PFS] and overall survival [OS]), clinicopathologic features, and denosumab treatment responsiveness. RESULTS: Low LIS was indicative of both poor PFS and OS (both P < .001). In addition, LIS was significantly associated with sex (P = .046), Enneking staging (P < .001), Ki-67 expression (P = .007), and denosumab treatment responsiveness (P = .005). Lower CD8+ (tumor interior [TI]) NNDTC, and CD3+ (TI) NNDTC were associated with worse PFS (P = .003 and .038, respectively), whereas lower CD8+ (TI) NNDTC was associated with worse OS (P = .001), but CD8+ (tumor infiltrating margin) NNDTC had the opposite effect (P = .002). Moreover, NNDTC showed a correlation with several clinicopathologic features. Importantly, LIS outperformed Enneking and Campanacci staging systems in predicting the clinical outcomes of GCTB. CONCLUSION: These findings suggest that LIS is a reliable predictive tool for clinically relevant outcomes and response to denosumab therapy in patients with GCTB. These parameters may prove to be useful in guiding prognostic risk stratification and therapeutic optimization for patients.

Combined preoperative denosumab and adjuvant microwave ablation for high-risk giant cell tumor of bone: a retrospective study in a single center.

BACKGROUND: Giant cell tumor of bone (GCTB) is a locally aggressive neoplasm with a high propensity for recurrence following intralesional curettage. The introduction of denosumab, a RANKL inhibitor, has shown potential in facilitating joint-sparing surgery. However, concerns exist regarding its impact on local recurrence rates. This study aimed to evaluate the efficacy and safety of combined preoperative denosumab with adjuvant microwave ablation (MWA) for the treatment of high-risk GCTB. METHODS: We conducted a retrospective review of 19 patients with high-risk GCTB who underwent preoperative denosumab treatment followed by curettage and adjuvant MWA. The primary outcome measure was the local recurrence rate, with secondary outcomes including functional status assessed by the Musculoskeletal Tumor Society (MSTS) score and safety profile of the treatment. RESULTS: In this retrospective analysis, we evaluated the outcomes of 19 patients with high-risk GCTB treated with preoperative denosumab and adjuvant MWA. The median follow-up duration was 33.1 months, 3 patients (15.8%) experienced local recurrence at a median of 21.6 months postoperatively and the local recurrence-free survival was 81.2% at two years. Notably, no patient developed lung metastasis, and all recurrences were successfully managed with repeat curettage and MWA, with a mean MSTS score of 27.3. No patient required joint replacement due to tumor recurrence, resulting in a 100% joint preservation rate. CONCLUSION: The combination of preoperative denosumab and adjuvant MWA is a feasible and effective strategy for the management of high-risk GCTB, providing effective local control with preserved joint function. This approach may offer a surgical alternative for young patients where joint preservation is paramount.

Validity of the Musculoskeletal Tumor Society Score for lower extremity in patients with bone sarcoma or giant cell tumour of bone undergoing bone resection and reconstruction surgery in hip and knee.

BACKGROUND: The Musculoskeletal Tumor Society Score (MSTS) is widely used to evaluate functioning following surgery for bone and soft-tissue sarcoma. However, concerns have been raised about its content validity due to the lack of patient involvement during item development. Additionally, literature reports inconsistent results regarding data quality and structural validity. This study aimed to evaluate content, structural and construct validity of the Danish version of the MSTS for lower extremity (MSTS-LE). METHODS: The study included patients from three complete cohorts (n = 87) with bone sarcoma or giant cell tumour of bone who underwent bone resection and reconstruction surgery in hip and knee. Content validity was evaluated by linking MSTS items to frameworks of functioning, core outcome sets and semi-structured interviews. Data quality, internal consistency and factor analysis were used to assess the underlying structure of the MSTS. Construct validity was based on predefined hypotheses of correlation between the MSTS and concurrent measurements. RESULTS: Content validity analysis revealed concerns regarding the MSTS. The MSTS did not sufficiently cover patient-important functions, the item Emotional acceptance could not be linked to the framework of functioning, the items Pain and Emotional acceptance pertained to domains beyond functioning and items' response options did not match items. A two-factor solution emerged, with the items Pain and Emotional acceptance loading highly on a second factor distinct from functioning. Internal consistency and construct validity showed values below accepted levels. CONCLUSION: The Danish MSTS-LE demonstrated inadequate content validity, internal consistency, and construct validity. In addition, our analyses did not support unidimensionality of the MSTS. Consequently, the MSTS-LE is not a simple reflection of the construct of functioning and the interpretation of a sum score is problematic. Clinicians and researcher should exercise caution when relying solely on MSTS scores for assessing lower extremity function. Alternative outcome measurements of functioning should be considered for the evaluation of postoperative function in this patient group.

The Role of Denosumab Treatment in Recurrent Giant Cell Bone Tumor of the Orbit.

Giant cell tumor of the bone (GCTB) is a rare primary bone neoplasm, representing about 5% of all primary bone tumors. Most GCTBs are found in the epiphysis of long bones, with only 2% of GCTBs involving the skull. In recent years, the receptor activator of nuclear factor Kappa ligand monoclonal antibody denosumab has been demonstrated as a promising therapeutic option for GCTB; however, this is an evolving field. We present a case of a 57-year-old female with a rare GCTB in the right orbit and sinuses, originally thought to be an aneurysmal bone cyst. Her symptoms included proptosis, intermittent blurry vision, sinus congestion, and frontal headaches. After excision, the tumor recurred within 18 months. Upon repeat excision, a diagnosis of GCTB was made. The patient started denosumab therapy and had no tumor growth over the ensuing 2 years, with stability of symptoms and clinical signs on follow-up.

The diagnostic and prognostic value of tartrate-resistant acid phosphatase isoform 5b for giant cell tumor of bone.

BACKGROUND: Serum level of tartrate-resistant acid phosphatase 5b (TRACP5b) is an excellent serum marker of bone resorption. In patients with giant cell tumor of bone (GCTB), TRACP5b levels are reportedly elevated. This study investigated whether TRACP5b could be a diagnostic serum marker and be useful for detecting postoperative disease progression for GCTB. METHODS: Cohort 1: We abstracted data from 120 patients with TRACP5b measurements from our database: 49 patients with GCTB and 71 patients non-GCTB. We compared serum TRACP5b values between the GCTB and non-GCTB groups. Cohort 2 included 47 patients with GCTB who had more than 6 months of follow-up and multiple TRACP5b values. For patients with local recurrence, TRACP5b change rate was calculated by comparing the TRACP5b value just before progression (a) with the value at the time of progression (b): Change rate = [(b)-(a)]/(a). In the non-progression group, the change rate was calculated from the two consecutive TRACP5b values, (c) and (d): Change rate =[(c)-(d)]/(c). We compared TRACP5b change rates between the progression and non-progression groups. RESULTS: Cohort 1: The GCTB group had a significantly higher mean TRACP5b value (1756 ± 2021 mU/dL) than the non-GCTB group (415 ± 219 mU/dL) (p < 0.0001). Cohort 2: The mean TRACP5b change rate of the progression group was significantly higher than the non-progression group (8.53 ± 8.52 and 0.24 ± 0.27, respectively; p < 0.0001). CONCLUSION: TRACP5b is a useful diagnostic marker in GCTB. The rate of change in serum TRACP5b values is a highly sensitive marker for predicting local recurrence in GCTB.

The effect of preoperative embolization on giant cell tumors of the bone localized in the iliosacral region of the pelvis.

INTRODUCTION: Giant cell tumors of the bone (GCTB) are aggressive neoplasms, with rare occurrences in the posterior pelvis and sacral area. Surgical challenges in this region include the inability to apply a tourniquet and limited cementation post-curettage due to proximity to neurovascular structures, leading to potential complications. This case-control study explores the impact of preoperative embolization on GCTB located in the iliosacral region. METHODS: Five surgeries (January-December 2021) for pelvic GCTB (3 sacrum, 2 posterior ilium) were performed on four patients. Diagnosis was confirmed through preoperative CT-guided biopsies. One surgery involved curettage with PMMA cement filling, while four surgeries had curettage without cavity filling. Preoperative embolization of the tumor feeding vessel occurred approximately 16 h before surgery in two cases. Denosumab treatment was not administered. RESULTS: Tumor volume, assessed by preoperative MRI, was comparable between patients with and without preoperative embolization (p = .14). Surgeries without embolization had a mean intraoperative blood loss of 3250 ml, erythrocyte transfusion volume of 1125 ml, and a mean surgical time of 114.5 min for two surgeries. Surgeries with preoperative embolization showed a mean intraoperative blood loss of 1850 ml, no erythrocyte transfusion requirement, and a mean surgical time of 68 min. CONCLUSION: Curettage of GCTB in the posterior pelvis and sacrum presents challenges, with significant intraoperative blood loss impacting surgical time and transfusion needs. Preoperative embolization may be beneficial in reducing blood loss during surgery in these cases.

The tumor-stroma ratio in giant cell tumor of bone: associations with the immune microenvironment and responsiveness to denosumab treatment.

BACKGROUND: Currently, there is limited understanding regarding the clinical significance of the tumor-stroma ratio (TSR) in giant cell tumor of bone (GCTB). Hence, we aimed to investigate the distribution of TSR in GCTB and explore its correlation with various clinicopathologic factors, immune microenvironment, survival prognosis, and denosumab treatment responsiveness. METHODS: We conducted a multicenter cohort study comprising 426 GCTB patients treated at four centers. TSR was evaluated on hematoxylin and eosin-stained and immunofluorescent sections of tumor specimens. Immunohistochemistry was performed to assess CD3+, CD4+, CD8+, CD20+, PD-1+, PD-L1+, and FoxP3+ TIL subtypes as well as Ki-67 expression levels in 426 tissue specimens. These parameters were then analyzed for their correlations with patient outcomes [local recurrence-free survival (LRFS) and overall survival (OS)], clinicopathological features, and denosumab treatment responsiveness. RESULTS: Low TSR was significantly associated with poor LRFS and OS in both cohorts. Furthermore, TSR was also correlated with multiple clinicopathological features, TIL subtype expression, and denosumab treatment responsiveness. TSR demonstrated similar predictive capabilities as the conventional Campanacci staging system for predicting patients' LRFS and OS. CONCLUSION: The results of this study provide evidence supporting the use of TSR as a reliable prognostic tool in GCTB and as a predictor of denosumab treatment responsiveness. These findings may aid in developing individualized treatment strategies for GCTB patients in the future.

Giant cell tumor of femur with single pulmonary metastasis - yet another curative oligometastasis.

ABSTRACT: Giant cell tumor of bone (GCT) is a benign tumor of bone that is known to be locally aggressive rarely metastasizing to distant sites, most commonly to the lungs. The reported pulmonary metastasis incidence is 1 - 9%. We report a case of GCT with solitary pulmonary metastasis who had significant clinical benefit and disease control with sequential application of surgical resection of pulmonary metastasis, local external beam radiation therapy (EBRT), and systemic Denosumab. We wish to highlight that even in metastatic GCT, there is significant clinical benefit in aggressive treatment.

Periprosthetic giant cell tumour of the tibia: en bloc resection and megaprosthesis revision.

We present a case detailing the diagnosis and management of a periprosthetic giant cell tumour in a female patient in her 70s, who had undergone total knee arthroplasty (TKA) for primary osteoarthritis in her right knee 7 years prior. The patient reported 4 months of painful weight-bearing. Various imaging modalities, including plain radiographs, CT scans and MRI, revealed a sizeable lytic lesion beneath the TKA prosthesis, along with loosening of the tibial component.Blood tests and analyses of synovial fluid ruled out periprosthetic joint infection, and a biopsy confirmed the diagnosis of a giant cell tumour of the bone. Treatment entailed en bloc resection of the tumour and revision of the TKA using a hinged, oncological-type megaprosthesis. Surgical procedures involved careful resection of the proximal tibia, preservation of vasculature and the creation of a medial gastrocnemius muscle flap. Following surgery, the patient underwent supervised rehabilitation with a functional brace.

Keratin-Positive Giant Cell Tumor of Bone and Soft Tissue With HMGA2::NCOR2 Fusion in Children Under 10 With Response to Imatinib Therapy: A Case Series.

HMGA2::NCOR2 keratin-positive giant cell tumors in children with response to imatinib in an infant.

Tumor de células gigantes esternal: esternectomía total y reconstrucción con barras de titanio más malla de polipropileno / Sternal Giant Cell Tumor: Total Sternectomy and Reconstruction with Titanium Rods Plus Polypropylene Mesh

El tumor de células gigantes (TCG) constituye un tumor óseo benigno relativamente frecuente. Se caracteriza por ser localmente agresivo y el lugar de presentación más frecuente es a nivel del esqueleto axial (fémur distal o tibia proximal). Hasta la actualidad, existen escasos informes de presentaciones atípicas, como a nivel del esternón. En este informe, se presenta el caso de una paciente mujer de 24 años que presenta tumoración indurada a nivel de la región esternal de crecimiento progresivo asociado a dolor. Los hallazgos radiológicos revelan tumoración osteolítica que tiene como origen el cuerpo del esternón y lo compromete casi en su totalidad. Este se proyecta hacia las partes blandas y llega al plano superficial. Debido a la extensión de la enfermedad y al compromiso extenso en el cuerpo del esternón, se realiza la resección del cuerpo y manubrio esternal. El defecto es reconstruido con malla de polipropileno, barras de titanio, parche de epiplón y autoinjerto de piel; se obtiene una adecuada estabilidad de la caja torácica y resultados estéticos favorables. El caso tiene un adecuado manejo oncológico puesto que la resección es completa con márgenes microscópicos libres (resección R0).

Giant cell tumor (GCT) constitutes a relatively common benign bone tumor, characteri-zed by its local aggressiveness. The most frequent site of occurrence is in the axial ske-leton (distal femur or proximal tibia). To date, there have been few reports of atypical presentations, such as at the level of the sternum. In this report, we present the case of a 24-year-old female patient who presented with an indurated mass in the sternal region, progressively growing and associated with pain. Radiological findings revealed an osteolytic mass originating from the body of the sternum, involving almost its entire extent and projecting into the soft tissues, reaching the superficial plane. Due to the extent of the disease and the extensive involvement of the sternal body, resection of the body and manubrium of the sternum was performed. The surgical defect was reconstructed with polypropylene mesh, titanium bars, an omental patch and a skin graft, achieving adequate stability of the thoracic cage and favorable cosmetic results.

En bloc resection and iliac crest bone grafting for giant cell tumor of the finger.

A case of a rapidly progressing giant cell tumor of the middle phalanx is presented. The patient underwent en bloc resection with iliac crest grafting and distal interphalangeal fusion. Surgical technique and patient's functional outcomes are described.

H3.3-G34W in giant cell tumor of bone functionally aligns with the exon choice repressor hnRNPA1L2.

RNA processing is an essential post-transcriptional phenomenon that provides the necessary complexity of transcript diversity prior to translation. Aberrations in this process could contribute to tumourigenesis, and we have previously reported increased splicing alterations in giant cell tumor of bone (GCTB), which carries mutations in the histone variant H3.3 encoding glycine 34 substituted for tryptophan (H3.3-G34W). G34W interacts with several splicing factors, most notably the trans-acting splicing factor hnRNPA1L2. To gain a deeper understanding of RNA processing in GCTB and isogenic HeLa cells with H3.3-G34W, we generated RNA-immunoprecipitation sequencing data from hnRNPA1L2 and H3.3-G34W associated RNAs, which showed that 80% overlapped across genic regions and were frequently annotated as E2F transcription factor binding sites. Splicing aberrations in both GCTB and HeLa cells with H3.3-G34W were significantly enriched for known hnRNPA1L2 binding motifs (p value < 0.01). This splicing aberration differed from hnRNPA1L2 knockouts, which showed alterations independent of H3.3-G34W. Of functional significance, hnRNPA1L2 was redistributed to closely match the H3.3 pattern, likely driven by G34W, and to loci not occupied in normal parental cells. Taken together, our data reveal a functional overlap between hnRNPA1L2 and H3.3-G34W with likely significant consequences for RNA processing during GCTB pathogenesis. This provides novel opportunities for therapeutic intervention in future modus operandi.

Diaphyseal giant cell tumour of mid-shaft tibia.

SummaryGiant cell tumours of bone are benign and locally aggressive tumours that usually occur in young adults and at the epiphysial locations after physeal closure. Occurrence outside of epiphysial locations and appearance in geriatric patients is rare. We report a case of a woman in her late 60s with a giant cell tumour of the mid-shaft of the right tibia. Extended curettage and biological reconstruction were performed with autologous double-barrel fibular struts and tri-cortical iliac crest bone grafting. At the 28-month follow-up examination, we noted full bony union at both ends with successful consolidation of the fibular struts, and importantly, no evidence of recurrence or other complications was observed.

Intralesional curettage and surgical adjuvants in the treatment of giant cell tumor of bone: meta-analysis and systematic review.

BACKGROUND: The ideal treatment for giant cell tumor of bone (GCTB) is still controversial. Various surgical adjuvants have been introduced following intralesional curettage to improve local control rates. However, findings from relevant studies are inconsistent, and no consensus has been reached. The purpose of this study is to determine what intraoperative adjuvant is effective in decreasing the recurrence of GCTB. METHODS: We performed a systematic review and meta-analysis of articles published in the PubMed and Embase electronic databases which assessed the recurrence rate of GCTB following intralesional curettage with or without various surgical adjuvants. Two authors independently evaluated all publications. Meta-analysis was performed with Stata/MP (Version 17.0, StataCorp LLC, TX, USA) and Review Manager (RevMan, Version 5.4.1, The Cochrane Collaboration, 2020). Pooled risk ratio (RR) was used for analysis, with P values less than 0.05 considered statistically significant. RESULTS: Twenty-four studies involving 2,579 patients were included in this analysis. The overall recurrence rates for patients treated with or without high-speed burring (HSB) are 11.9% (26/218) and 47.7% (92/193), respectively. The pooled RR for tumor recurrence is 0.33 (95% CI: 0.22 to 0.49, P<0.001). In the meanwhile, the overall recurrence rates for patients treated with or without chemical adjuvants are 23.5% (77/328) and 26.1% (73/280), respectively, with a pooled RR of 0.84 (95% CI: 0.63 to 1.10, P=0.89). Additionally, the overall recurrence rates for patients treated with or without polymethyl methacrylate (PMMA) are 20.4% (205/1,006) and 33.4% (314/939), respectively, with a pooled RR of 0.59 (95% CI: 0.50 to 0.69, P<0.001). CONCLUSIONS: Intraoperative application of HSB or PMMA has an additional antitumor effect, while the use of phenol or H2O2 fails to make any significant difference (PROSPERO: CRD42022344262).

The Evaluation and Management of Lung Metastases in Patients with Giant Cell Tumors of Bone in the Denosumab Era.

Giant cell tumor of bone (GCTB) is characterized by uncertain biological behavior due to its local aggressiveness and metastasizing potential. In this study, we conducted a meta-analysis of the contemporary literature to evaluate all management strategies for GCTB metastases. A combination of the terms "lung metastases", "giant cell tumor", "bone", "treatment", and "oncologic outcomes" returned 133 patients meeting our inclusion criteria: 64 males and 69 females, with a median age of 28 years (7-63), at the onset of primary GCTB. Lung metastases typically occur at a mean interval of 26 months (range: 0-143 months) after treatment of the primary site, commonly presenting as multiple and bilateral lesions. Various treatment approaches, including surgery, chemotherapy, radiotherapy, and drug administration, were employed, while 35 patients underwent routine monitoring only. Upon a mean follow-up of about 7 years (range: 1-32 years), 90% of patients were found to be alive, while 10% had died. Death occurred in 25% of patients who had chemotherapy, whereas 96% of those not treated or treated with Denosumab alone were alive at a mean follow-up of 6 years (range: 1-19 years). Given the typically favorable prognosis of lung metastases in patients with GCTB, additional interventions beyond a histological diagnosis confirmation may not be needed. Denosumab, by reducing the progression of the disease, can play a pivotal role in averting or delaying lung failure.