Response to Denosumab in 2 Children With Recurrent Giant Cell Tumor of the Bone With Pulmonary Metastasis.

Giant cell tumor of the bone (GCTB) is an uncommon bone tumor, usually localized, and rarely presents at <20 years of age. Denosumab, a fully human monoclonal antibody against RANKL (receptor activator of nuclear factor κB ligand), is approved for the treatment of unresectable GCTB in skeletally mature individuals. We present a case series of 2 pediatric patients with recurrent GCTB with pulmonary metastasis, with clinical response to denosumab therapy.

Bilateral Lung Metastases From a Phalangeal Giant Cell Tumor of Bone.

We describe a rare pediatric case of a phalangeal giant cell tumor of bone with extensive bilateral lung metastases following curettage, wide resection, and amputation. Concurrent peripheral blood eosinophilia and pleural effusion with marked eosinophilia (47%) were present. To discover genetic changes driving tumor metastasis, genomic and transcriptome profiling of the metastatic lung mass as well as germline analysis were performed. Whole exome sequencing detected a histone H3F3A p.G35V missense mutation in tumor cells. RNA sequencing revealed overexpression of receptor activator of nuclear factor kappa-B ligand (RANKL). The patient is alive with no residual disease and uncompromised respiratory function 29 months after amputation of primary tumor and 19 months after surgical resection of his metastatic lung disease.

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

PURPOSE: 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. MATERIALS AND METHODS: We retrospectively studied 381 GCT patients with surgery alone and 30 GCT patients with surgery and denosumab administration. The median follow-up was 85.2 months (IQR, 54.2-124.4 months). We evaluated lung metastases and local recurrences, univariate and multivariate predictors for lung metastases, response, and adverse events of denosumab administration. RESULTS: 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. CONCLUSION: 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.

What are the Functional Results, Complications, and Outcomes of Using a Custom Unipolar Wrist Hemiarthroplasty for Treatment of Grade III Giant Cell Tumors of the Distal Radius?

PURPOSE: A giant cell tumor (GCT) of bone presenting in the distal radius is rare, however, when they occur, Campanacci Grade III tumors can present formidable reconstructive challenges. They are associated with a high local recurrence rate with intralesional treatment, therefore approaches to reconstruct the wrist after en bloc resection warrant study. QUESTIONS: We asked: (1) What are the functional outcomes after en bloc resection and reconstruction of the wrist with a unipolar prosthesis in patients with Grade III GCT of the distal radius? (2) What complications occur with use of a unipolar prosthesis in these patients? (3) What are the oncologic outcomes with using en bloc resection and reconstruction with a custom unipolar wrist hemiarthroplasty for Grade III GCTs of the distal radius? METHODS: We retrospectively analyzed 10 patients with Campanacci Grade III GCTs of the distal radius treated by a unipolar prosthesis after wide resection of the tumor between January 2008 and October 2013. During that period, all patients at our medical group who presented with a Grade III GCT of the distal radius were treated with wide resection and reconstruction using a custom unipolar implant. Pre- and postoperative pain at rest were assessed according to a 10-cm VAS score. The functional outcomes of the wrist were assessed using the modified Mayo wrist score, and the degenerative changes were evaluated radiographically by a new rating system based on the Knirk and Jupiter scale. We also analyzed tumor recurrence, metastases, and complications associated with the reconstruction procedure. All patients were available for followup at a mean of 52 months (range, 24-90 months). RESULTS: Although the complication rate associated with prosthetic arthroplasty was relatively high (six of 10), none of our patients experienced severe complications. Two patients reported having occasional pain of the involved wrist at the time of final followup (VAS, preoperative versus postoperative: 0 versus 3; 5 versus 2, respectively). The mean modified Mayo wrist score was 68 (range, 45-90). Degenerative changes were found in three wrists (Grade 1, two patients; Grade 2, one patient). Aseptic loosening occurred in one patient and wrist subluxation occurred in two patients. Lung metastases or local tumor recurrence were not observed. CONCLUSIONS: Because of the proportion of patients who had complications and progressive degeneration with this approach, we recommend first exploring alternatives to reconstruction with custom unipolar wrist hemiarthroplasty after resection of Grade III GCTs of the distal radius, such as fibular autografting. However, this technique provides an alternative for patients with concerns regarding possible morbidity associated with autografting, and for situations when allograft is not available. LEVEL OF EVIDENCE: Level IV, therapeutic study.

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.

Iatrogenic implantation of giant cell tumor at bone graft donor site and clinical recommendations to prevent "a rare avoidable complication".

The treatment of giant cell tumor of bone is directed toward local control without sacrificing joint function. This is achieved by intralesional curettage. When autograft is used for the reconstruction of the curetted cavity, there is always a theoretical risk of contamination of graft donor site. We report a case of iatrogenic implantation of giant cell tumor at the bone graft donor site after intralesional curettage and bone grafting of giant cell tumor of distal femur. Patient was treated with repeat intralesional curettage and excision of implantation lesion at bone graft donor site. We recommend precautionary measures to prevent this avoidable complication.

Local adjuvants in surgical management of bone metastases.

Curettage is one of the most common method for surgical treatment of bone metastasis. Local adjuvant improve most commonly used for improving the effect of curettage in local cancer surgery may exerted their effects either chemically either physically; in Orthopedic Oncology the most common are phenol, liquid nitrogen, laser, and cement. This article reviewed the main characteristics of the most common chemical and physical agents used in bone oncology, emphasizing the toxic effects of some of them, especially phenol and liquid nitrogen.

Giant cell tumor of bone: risk factors for recurrence.

BACKGROUND: 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. QUESTIONS/PURPOSES: 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. METHODS: 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). RESULTS: 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. CONCLUSION: 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.

Differential gene expression in classic giant cell tumours of bone: Tenascin C as biological risk factor for local relapses and metastases.

AIMS: To identify candidate prognostic biological markers useful in selecting high-risk patients with classic primary giant cell tumours (GCT). GCT specimens with different behaviour associated with an increased risk of local and/or distant relapses were studied. METHODS AND RESULTS: Screening mRNA microarray analysis followed by real-time polymerase chain reaction and immunohistochemistry on tissue microarray sections was used to validate the prognostic role of differentially expressed genes on a larger series by statistical analysis tests. Global gene expression profiling identified 109 differentially expressed genes according to prognosis. A correlation was found between mRNA levels and clinical outcome identifying Tenascin C (TNC) as the most significant prognostic biological marker. By means of backward Wald logistic regression, TNC overexpression defined an eightfold increased risk for metastasis and fourfold for local recurrence. At the protein level, TNC immunoreactivity resulted in a significant difference in the disease-free survival probability curves, providing a stratification for GCT patients, useful for predicting relapse. CONCLUSIONS: Our study provides important data for the selection of biomarkers with a significant clinical impact and suggests the importance of TNC expression in identifying GCT patients at a higher risk of relapse for closer follow-up and adjuvant medical therapy.

Metastatic giant cell tumor of bone: are there associated factors and best treatment modalities?

UNLABELLED: Giant cell tumors of bone are sometimes locally aggressive and may metastasize, although uncommonly. We attempted to identify associations of clinical and histopathologic parameters with metastasis, the long-term outcome with metastases, and the best treatment. We identified distant metastases in 24 of 470 patients with giant cell tumors during a 20-year period. The median age of these 24 patients at presentation was 26 years (range, 16-76 years), and the male:female ratio was 1.6:1, with no predilection for primary site. Metastasis occurred at a mean of 2 years (range, 4 months-11 years) after initial diagnosis. Sites for distant metastases were the lung (21 of 24 patients), scalp, calf muscle, and regional lymph nodes. The 24 patients had a mean followup of 3.5 years (range, 0-16 years). Thirteen of the 24 patients has local recurrence before or at the time of metastasis. Two patients refused treatment, eight underwent metastasectomy, and 14 were inoperable (four had chemotherapy, 10 were treated symptomatically). We observed disease progression with hemoptysis in one of 14 patients. None of the patients died of their metastatic disease. None of the risk factors we studied was associated with metastasis in giant cell tumors. Although the overall outcome was favorable, metastasectomy is recommended where feasible. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Metachronous multicentric giant cell tumour of the upper extremity in a skeletally immature girl : A rare presentation.

Giant Cell tumour (GCT) or Osteoclastoma is a benign locally aggressive tumour with a tendency for local recurrence. Long tubular bones (75-90%) are frequent sites of involvement. GCT constitutes 5% of all primary bone tumours. Metachronous multicentric giant cell tumour of bone is a rare entity. Multicentric GCT, in contrast to unifocal GCT, has a tendency to involve the small bones of hands and feet, involving the metaphysis/diaphysis of long bones and tends to occur in a slightly younger population. We report a young girl presenting with metachronous multicentric recurrent benign GCT, with the lesions involving the ipsilateral right hand and distal humerus. She was successfully treated with an aggressive surgical approach (en-bloc resection).

Locally Aggressive Giant Cell Tumor of Bone With Pulmonary Distant Metastasis and Extrapulmonary Seeding in Pregnancy.

Giant cell tumor of bone (GCTB) is a locally aggressive benign neoplasm that is associated with a large biological spectrum ranging from latent benign to highly recurrent and occasionally metastatic tumor. In this article, we present a case of a 26-year-old woman who presented with swelling at the left lower ribs during pregnancy. Surgical excision was done, and histopathology showed tumor with features consistent with GCTB. MRI preformed after delivery revealed recurrence of the mass with extensive growth reaching 17 cm with two subcutaneous satellite nodules in the adjacent abdominal wall. positron emission tomography-computed tomography (PET-CT) scan revealed bilateral fluorodeoxyglucose (FDG)-avid lung nodules. Surgical resection was done, and histopathology showed no evidence of malignant transformation. Few months later, the tumor recurred again, with peritoneal deposits. The patient underwent wide massive resection of the recurrent mass and then started on denosumab therapy. Molecular analysis of the tumor detected H3F3A G34W mutation with no copy number alterations. We are presenting this case of GCTB with pulmonary distant metastasis and extrapulmonary seeding to upsurge awareness among clinicians about the possible extreme aggressive biological behavior of GCTB that can mimic the presentation of malignant bone tumor and also to discuss the possible predictive factors of such aggressive behavior.

Metastatic behaviour of giant cell tumour of the spine.

Lung metastases from giant cell tumours (GCT) of the spine have not been specifically addressed in the literature. We reviewed our cases and compared the incidence, treatment, and outcomes with those from the extremities. Between 1970 and 2006, we identified seven cases (three females and four males) of lung metastases from a total of 51 cases of GCT of the spine (13.7%). Four of the seven patients had presented to our institution with a spine recurrence after previous treatments and the rest developed recurrences later. The treatments for the lung nodules consisted of metastectomy in two and chemotherapy in six patients. At the latest follow-up (ranging from 18 to 126 months), two had died of the disease, two had no evidence of the disease, and three were alive with disease. Our series shows a higher metastatic rate from spine GCT as compared to those from the extremities, but the overall behaviour and treatment outcomes of the lung metastases are similar. When there is a recurrence of GCT, with or without metastases, the local and possibly the metastases should be biopsied to confirm the original diagnosis. Progression of benign GCT into an aggressive sarcoma has been documented, and the method of management should be altered.

Curettage and allograft reconstruction for giant cell tumours.

PURPOSE: To evaluate treatment outcomes in patients with giant cell tumours after curettage and allograft reconstruction and to identify the risk factors for poor oncological and functional outcome. METHODS: 29 patients with giant cell tumours of bone who underwent curettage and allograft reconstruction were retrospectively reviewed. The adjuvants used were heat treatment by electrocautery and hot water. Types of allograft used, time to bone union, complications, functional outcomes, and risk factors for poor function were analysed. RESULTS: The mean time to bone union was 2.8 (range, 1-5) months. In 7 patients the tumours recurred (6 within 2 years); the 5-year recurrence-free survival rate was 77%. Three recurrences were classified as grade III and 4 as grade II; recurrence and the Campanacci grade showed a trend towards association (p=0.06). Tumour in the distal femur was a risk factor for postoperative fracture (p=0.02). Functional outcomes were excellent in 20 patients, good in 6, fair in 2, and a failure in one. The risk factors for poor function were recurrence (p=0.002) and joint instability (p=0.008) but not the Campanacci grade (p=0.10) or postoperative fracture (p=0.76). Lung metastasis, infection, and non-union were not encountered. CONCLUSION: Despite a relatively high recurrence rate (24%), 26 (90%) of the 29 patients had excellent/good functional outcomes. We recommend the use of adjuvants and allografts for the management of giant cell tumours.

A rare case of giant cell tumour (GCT) of bone with lung metastases.

A case of 16-year-old girl with giant cell tumour of right fibula is presented to us with bilateral lung metastases. In view of widespread bilateral lung metastatic lesions, the patient was given multimodality treatment. Chemotherapy followed by radiotherapy to the local site as well as lung bath has been given and has shown good response.

Detection of H3F3A p.G35W and p.G35R in giant cell tumor of bone by Allele Specific Locked Nucleic Acid quantitative PCR (ASLNAqPCR).

Giant Cell Tumor (GCT) represents about 20% of benign bone tumors, is locally aggressive although malignant transformation is extremely rare, <1% of cases but 2-3% give pulmonary metastasis. Age at onset is between 20 and 40 years with a slight predominance for the female gender. GCT is characterized by specific mutations in H3F3A gene encoding the protein histone 3.3. The study of these mutations is important for the differential diagnosis with giant cell rich sarcomas, chondroblastoma and aneurysmal bone cyst. To identify the most frequent H3F3A mutations we developed a novel allele specific Real Time Polymerase Chain Reaction method, based on Allele Specific Locked Nucleic Acid (ASLNAqPCR) that is here described. Molecular analyses were performed on 20 GCT and 2 osteosarcoma arising on a previous GCT. All cases were verified by Sanger sequencing. We demonstrated that ASLNAqPCR is a quick, sensitive and reliable method to identify mutations of the H3F3A gene, in giant cell tumor of bone, to support diagnosis in morphologically ambiguous cases.

Giant cell tumor of bone: updated molecular pathogenesis and tumor biology.

Giant cell tumor of bone (GCTB)-related clonal aberrations occur in a background of epigenetic histone modifications (especially the G34W mutation of H3F3A gene) that induce cytogenetic abnormalities. Clonal aberrations are closely linked to the aggressiveness of GCTB. The "neoplastic" mononuclear stromal cells in GCTB express fundamental RANKLs and various chemokines and cytokines associated with monocyte recruitment and "reactive" multinucleated giant cells (osteoclastogenesis). The reciprocal and orchestrated actions between mononuclear stromal cells and multinucleated giant cells help in the understanding of the molecular pathogenesis and tumor biology of GCTB. In the future, novel targets in the updated tumor biology and molecular pathogenesis of GCTB should be explored and scrutinized for the development of systemic therapy.

Histone 3.3 mutations in giant cell tumor and giant cell-rich sarcomas of bone.

Mutually exclusive histone 3.3 gene mutations have been recognized in chondroblastoma and giant cell tumor of bone (GCTB), which may be useful for differential diagnostic purposes in morphologically ambiguous cases. Although more than 90% of GCTBs present histone 3.3 variants exclusively in the H3F3A gene, chondroblastoma is mutated mainly in H3F3B. In this study, we examined a series of giant cell-rich primary bone tumors, aiming to evaluate the possible diagnostic role of histone 3.3 mutations in the differential diagnosis between GCTB and giant cell-rich sarcomas. Sixteen cases of nonmetastatic GCTB, 9 GCTBs with lung metastases, and 35 giant cell-rich sarcomas were selected from our institutional archives. Eight chondroblastomas were used as controls. Direct sequencing for the presence of H3F3A and H3F3B variants in coding region between codons 1 and 42, including the hotspot codons (28, 35, and 37), was performed on DNA extracted from formalin-fixed, paraffin-embedded tissue using conventional polymerase chain reaction and fast coamplification at lower denaturation temperature-polymerase chain reaction. Overall, 24 GCTBs (96%) presented a mutation in the H3F3A gene (15 of 16 nonmetastatic and 9 of 9 metastatic). Five sarcomas harbored an H3F3A mutation (3 p.G35W, 1 p.G35L, and 1 p.G35E), and these were all secondary malignant GCTBs. In conclusion, we confirm that H3F3A mutational testing may be a useful adjunct to differentiate GCTB from giant cell-rich sarcomas. Although the presence of H3F3A mutations does not exclude with certainty a diagnosis of sarcoma, the possibility of a malignant evolution of GCTB should also be considered.

Denosumab in advanced/unresectable giant-cell tumour of bone (GCTB): For how long?

BACKGROUND: Giant-cell tumours of bone (GCTB) are RANK/RANK-ligand (RANKL) positive, aggressive and progressive osteolytic tumours. Denosumab, a RANKL inhibitor, was FDA-approved for adults and skeletally mature adolescents with unresectable GCTB or when surgical resection is likely to result in severe morbidity. Data on long-term toxicity and activity of denosumab monthly 'GCTB-schedule' (120 mg per 12/year, 1440 mg total dose/year) are lacking. METHODS: Patients with GCTB receiving denosumab, 120 mg on days 1, 8, 15, 29 and every 4 weeks thereafter, from 2006 to 2015 treated in two centres were included. Long-term toxicity was evaluated. RESULTS: Ninety-seven patients were identified. 43 patients underwent resection of the tumour with a median time on denosumab treatment of 12 months (range 6-45 months). Fifty-four patients had unresectable GCTB's (male/female 23/31, median age 35 years [range: 13-76 years], 26% presented with lung metastases, 31% had primary tumor located to the spine, 63% were relapsed after previous surgery) with a median time on denosumab of 54 months (9-115 months). In the unresectable GCTB group, tumour control and clinical benefits were observed in all patients undergoing denosumab, whereas 40% of patients discontinuing denosumab had tumour progression after a median of 8 months (range 7-15 months). ADVERSE EVENTS: Overall, six (6%) patients developed osteonecrosis of jaw (ONJ): 1/43 (2%) in the resectable group, 5/54 (9%) in the unresectable group, with a 5-year ONJ-free survival of 92% (95% CI 84-100). Only patients with prolonged treatment experienced mild peripheral neuropathy (6/54, 11%), skin rash (5/54, 9%), hypophosphataemia (2/54, 4%) and atypical femoral fracture (2/54, 4%). CONCLUSIONS: Prolonged treatment with denosumab has sustained activity in GCTB, with a mild toxicity profile. The dose-dependent toxicity observed recommends a careful and strict monitoring of patients who need prolonged treatment. Decreased dose-intensity schedules should be further explored in unresectable GCTB.