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.

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.

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.

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.

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.

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.

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.

Wide resection versus curettage with adjuvant therapy for giant cell tumour of bone.

PURPOSE: To determine the association between type of surgery (wide resection versus curettage with adjuvant therapy) and outcome in patients with giant cell tumour (GCT) of bone. METHODS: Records of 30 male and 52 female consecutive patients aged 10 to 62 years who underwent wide resection (n=57) or curettage with adjuvant therapy (n=25) for primary GCT of bone were reviewed. The surgical decision was based on patient age, tumour location, functional demand, and patient preference. The median tumour size was 8.5 cm. Tumours were classified as stage 1 (n=4), stage 2 (n=60), and stage 3 (n=18), and 25%, 68.3%, and 83.3% of them were treated with wide resection, respectively. Functional outcome was assessed using the Musculoskeletal Tumor Society (MSTS) score; the maximum score was 30. RESULTS: The wide resection and curettage with adjuvant therapy groups were comparable in terms of patient age, gender, tumour size, location, symptoms, tumour stage, type of biopsy, and MSTS score. The MSTS score was excellent in 50.2% of patients, good in 38.7% of patients, and fair and poor in the remaining patients. The MSTS score was not associated with tumour stage or type of surgery. Four patients in the wide resection group had metastasis to the lung. They also had lower haemoglobin level (10.6 vs. 12.7 g/dl, p=0.020) and higher percentage of stage-3 tumour (100% vs. 17.9%, p=0.001) but had no recurrence (0% vs. 6.4%, p=0.774), compared with those without metastatsis. All died from massive haemoptysis and respiratory failure. Eight patients died; their haemoglobin level was lower than that of patients who were still living (11.2 vs. 12.7 g/dl, p=0.032). Mortality was associated with metastasis (100% vs 5.2%, p<0.001) but not recurrence or complication. Two patients in each group had recurrence; recurrence was not associated with type of surgery. CONCLUSION: There was no association between type of surgery and tumour recurrence, metastasis, or outcome. Curettage with adjuvant therapy was more commonly performed for stage 1 and 2 tumours, whereas wide resection was more for stage 3 tumours. Metastasis was associated with stage 3 tumour and mortality but not recurrence.

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.

Acute Onset of Vancomycin Anaphylaxis With Disseminated Intravascular Coagulation in an Orthopedic Patient Despite Prior Repeated Exposure.

Vancomycin is a glycopeptide antibiotic that exhibits bactericidal activity against gram-positive cocci. It is commonly recommended for surgical prophylaxis in cases of suspected bacterial resistance or penicillin allergy. There are 2 main types of hypersensitivity reactions associated with vancomycin. Red man syndrome is an anaphylactoid reaction caused by direct release of histamine. The second is an anaphylactic reaction, which is an immunoglobulin E-mediated response. We present the case of a 55-year-old woman with a history of metastatic giant cell tumor of the right proximal tibia. She had undergone multiple surgeries for this and other nonorthopedic conditions. The patient received vancomycin for the majority of these procedures and extended courses of vancomycin on 2 separate occasions. In the present case, the patient was taken to the operating room for a prosthetic infection, and vancomycin was given after cultures were taken. The patient immediately developed signs consistent with anaphylaxis and disseminated intravascular coagulation. This was treated acutely with hemodynamic resuscitation, replacement of blood components, steroids, and repeated boluses of epinephrine. She recovered and was taken back to the operating room during that same admission without incident. The patient has since been treated with systemic daptomycin and a tobramycin cement spacer without further incident.

Risk factors for pulmonary metastases from giant cell tumor of bone.

BACKGROUND: Giant cell tumor (GCT) of bone is a rare, benign, aggressive bone tumor with an unusual capacity to metastasize to the lung. It was the goal of this study to identify patient and treatment-specific variables associated with the development of pulmonary metastases of GCT of bone. METHODS: From 1980 to 2009, 291 patients with benign GCT of bone were treated at our institution, and 167 were followed for at least two years. Eleven (6.6%) of these 167 patients developed biopsy-confirmed pulmonary metastasis. All patients were evaluated relative to nine patient, disease, and treatment-specific variables. RESULTS: We identified four properties of benign GCT of bone associated with an increased risk of metastasis on univariate analysis: age at diagnosis, axial location of the primary GCT, primary Enneking stage-3 disease, and local recurrence. Multivariate analysis showed local recurrence to be an independent risk factor for pulmonary metastasis (adjusted odds ratio, 7.42). CONCLUSIONS: There is an increased risk of pulmonary metastasis of GCT of bone in patients who are younger, present with Enneking stage-3 disease, develop local recurrence, and/or present with axial disease. The mode of treatment was not found to be associated with the development of pulmonary metastasis.

Radiological and pathological characteristics of giant cell tumor of bone treated with denosumab.

We describe a case of giant cell tumor of the proximal tibia with skip bone metastases of the ipsilateral femur in a 20-year-old man. After the neoadjuvant treatment with denosumab, plain radiographs and computed tomography showed marked osteosclerosis and sclerotic rim formation, and 18F-FDG PET/CT showed a decreased standardized uptake value, whereas magnetic resonance imaging showed diffuse enhancement of the tumor, nearly the same findings as those at pretreatment. Pathological findings of the surgical specimen after the denosumab treatment showed benign fibrous histiocytoma-like features with complete disappearance of both mononuclear stromal cells and multinuclear osteoclast-like giant cells. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1090602085125068.

Giant cell tumor of bone presenting in the lumbar spine of a 35-year-old female: cytodiagnosis and other diagnostic considerations.

Fine-needle aspiration (FNA) is commonly used in the evaluation of both primary and metastatic bone lesions. Giant cell tumor (GCT) of bone is one of the primary bone neoplasms that can be diagnosed with good success on FNA as its cytologic features are relatively reproducible. However, this entity classically involves the ends (or epiphyses) of the longs bones making an FNA diagnosis of a GCT of bone in other anatomic locations is challenging and requires the consideration of a differential diagnosis. By invoking clinico-radiographical correlation and maximizing our specimen, we were able to diagnose a GCT of bone involving the L1 vertebral body in a 35-year-old female.

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.

MicroRNA expression profiles in metastatic and non-metastatic giant cell tumor of bone.

Giant cell tumor of bone (GCTB) is a skeletal neoplasm, a locally aggressive tumor that occasionally metastasizes to the lungs. To identify novel biomarkers associated with GCTB progression and metastasis, we performed a miRNA microarray on ten primary tumors of GCTB, of which five developed lung metastases and the rest remained metastasis-free. Between metastatic and non-metastatic GCTB, 12 miRNAs were differentially expressed (such as miR-136, miR-513a-5p, miR-494, miR-224, and miR-542-5p). A decreased level of miR-136 in metastatic versus non-metastatic GCTB was significantly confirmed by the quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) (p=0.04). To identify potential target genes for the differentially expressed miRNAs, we used three target prediction databases. Then, to functionally validate the potential target genes of the differentially expressed miRNAs, we re-analyzed our previous gene expression data from the same ten patients. Eight genes such as NFIB, TNC, and FLRT2 were inversely expressed relative to their predicted miRNA regulators. NFIB expression correlated in metastatic GCTB with no or low expression of miR-136, and this gene was selected for further verification with qRT-PCR and immunohistochemistry. Verification of NFIB mRNA and protein by qRT-PCR showed elevated expression levels in metastatic GCTBs. Further, the protein expression level of NFIB was tested in an independent validation cohort of 74 primary archival GCTB specimens. In the primary tumors that developed metastases compared to the disease-free group, NFIB protein was moderately to strongly expressed at a higher frequency. Thus, in GCTB, miR-136 and NFIB may serve as prognostic makers.

Pulmonary metastatic giant cell tumors presenting as totally hyalinized and ossified nodules.

We report a case of giant cell tumor of the left distal femur with simultaneous bilateral pulmonary metastases. Pathologic examination of the left lung nodule showed a metastatic giant cell tumor with a noncontinuous ossified rim, and the right lung nodules were totally hyalinized or ossified without residual giant cell tumor components. Hyalinization was a consistent finding in both the primary bone lesion and the pulmonary metastases. Because the patient did not receive chemotherapy or radiotherapy before her surgical procedure, we believe that these changes represent spontaneous tumor regression.

Giant cell tumor of the mobile spine: a review of 49 cases.

STUDY DESIGN: This is a retrospective review of 49 cases of giant cell tumor (GCT) of the mobile spine treated surgically. OBJECTIVE: Our goal was to determine which factors influenced local recurrence. SUMMARY OF BACKGROUND DATA: GCT is a benign, locally aggressive tumor that rarely occurs in the spine. The management of local recurrence can be challenging. METHODS: We performed a retrospective analysis of GCTs of the mobile spine managed between 1970 and 2005. Median follow-up was 145 months with a minimum of 2 years or until death. We used the Kaplan-Meier method to test whether Enneking stage, surgery type, and surgical margin had statistically significant impact on local recurrence. The log rank test was used for comparison, and a P value of less than 0.05 was deemed significant. RESULTS: Of the 49 patients, 11 (22%) local recurrences occurred. The latest recurrence occurred at 60 months. Age less than 25 years was associated with a worse relapse-free survival (P = 0.03). En bloc resection was associated with better local control with Enneking stage III tumors (P = 0.01); however, intralesional resection provided adequate control of Enneking stage II tumors. There were 6 (12%) cases of metastasis, and 2 patients died from the progression of their disease. One patient died from the complications of the surgery. CONCLUSION: En bloc resection should be considered for Enneking stage III GCTs of the mobile spine. The choice of en bloc resection must be balanced with the inherent risks of the procedure. Intralesional resection of Enneking stage II tumors provides adequate local control. Patients should be followed for at least 5 years because local relapse can occur late.