Making sense of giant cell lesions of the jaws (GCLJ): lessons learned from next-generation sequencing.

Next-generation sequencing has revealed mutations in several bone-related lesions and was recently used to uncover the genetic basis of giant cell lesions of the jaws (GCLJ). Consistent with their benign nature, GCLJ show a low tumor mutation burden. They also harbor somatic, heterozygous, mutually exclusive mutations in TRPV4, KRAS, or FGFR1. These signature mutations occur only in a subset of lesional cells, suggesting the existence of a 'landscaping effect', with mutant cells inducing abnormal accumulation of non-mutant cells that form the tumor mass. Osteoclast-rich lesions with histological similarities to GCLJ can occur in the jaws sporadically or in association with genetically inherited syndromes. Based on recent results, the pathogenesis of a subgroup of sporadic GCLJ seems closely related to non-ossifying fibroma of long bones, with both lesions sharing MAPK pathway-activating mutations. In this review, we extrapolate from these recent findings to contextualize GCLJ genetics and we highlight the therapeutic implications of this new information. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Minimally Invasive Spinal Stabilization with Denosumab before Total Spondylectomy for a Collapsing Lower Lumbar Spinal Giant Cell Tumor.

A 21-year-old man consulted our hospital for treatment of a spinal giant cell tumor (GCT) of Enneking stage III. Lower lumbar-spine tumors and severe spinal canal stenosis are associated with high risk for surgical mor-bidity. Stability was temporarily secured with a percutaneous pedicle screw fixation in combination with deno-sumab, which shrank the tumor. Total en bloc spondylectomy was then performed 6 months after initiation of denosumab, and the patient was followed for 3 years. There was no local recurrence, and bony fusion was obtained. Minimally invasive surgery and denosumab allowed safer and easier treatment of a collapsing lower lumbar extra-compartmental GCT.

Denosumab for Effective Tumor Size Reduction in Patients With Giant Cell Tumors of the Bone: A Systematic Review and Meta-Analysis.

BACKGROUND: Denosumab is a human monoclonal antibody that has been used successfully in the treatment of giant cell tumors of bone. These tumors are rare and, in principle, benign, but they are highly aggressive, locally advanced, osteolytic bone tumors that can metastasize to the lungs. Denosumab is an effective treatment when these tumors cannot be surgically removed or when surgical resection is likely to lead to severe morbidity (eg, loss of limbs or joints). The aim of this systematic review and meta-analysis was to investigate patients with giant cell tumors of bone who experienced tumor progression during treatment with denosumab and to compare them with patients who experienced reduction of their giant cell tumors of bone during treatment with denosumab. METHODS: Embase, Cochrane Library, and MEDLINE/PubMed databases were searched for trials submitted by January 7, 2020, that reported the efficacy and safety of denosumab in patients with giant cell tumors of bone. RESULTS: Sixty studies were reviewed, involving a total of 1074 patients who had giant cell tumors of bone and were treated with denosumab. Of the 60 studies, 58% of the patients were from case series studies, 39% from open-label phase II studies, and 3% from case reports. The response rate for denosumab as a treatment for giant cell tumors of bone was 97.5%, with statistical significance (P < .0001). Pain in the limbs was statistically the most common adverse event for denosumab treatment in case series studies (P < .0001). No treatment-related deaths occurred in the reviewed studies. CONCLUSION: Cumulative evidence supports the addition of surgery to optimal medical therapy with denosumab to reduce tumor size, clinical symptoms, and mortality among patients with giant cell tumors of bone.

Cryotherapy efficacy and safety as local therapy in surgical treatment of musculoskeletal tumours. A retrospective case series of 143 patients.

Cryotherapy, also called Cryoablation (CA), is a technique that provides a local treatment to various pathological conditions. In Musculoskeletal tumours management, Cryoablation is well accepted and validated as a treatment in palliative cures for metastatic patients. Recently, CA has been proposed also as an alternative to radiofrequency ablation in osteoid osteoma and other benign tumour treatment with promising results. Cryotherapy with argon ice-balls as local adjuvant in open surgery is a tool that can provide enlargement of surgical margins if used properly. There is still not enough evidence supporting use of cryotherapy as local adjuvant in Musculoskeletal open surgery as the series cited above are very small and there is no comparative RCT between local adjuvant therapies including CA. One-hundred-and-eighty-three patients were treated with Cryoablation from 2000 and 2018 in the Musculoskeletal Tumours Surgery Unit of Careggi (Florence) and the University 2nd Clinic of Pisa. In our study group, 38 patients (26.6%) were affected by bone metastasis, 16 patients (11.1%) by aneurismal bone cysts or angiomas, 22 patients (15.4%) by low-grade malignant musculoskeletal tumours, 2 patients (1,4%) by fibromatosis, 63 patients (44.1%) by benign musculoskeletal tumours (principally Giant Cell Tumours-GCT) and 2 patients (1.4%) by Osteosarcomas. In 125 cases (87.4%), CA has been used as an adjuvant therapy, in 12 cases (8.4%) as a percutaneous ablation therapy and in 6 cases (4.2%) as adjuvant to remove tumoral lesions 'en bloc' or as a 'poor technique' for its sterilizing effect on previously resected bones. Mean follow-up was 10 years. Twenty-three patients (16%) were classified as Alive with Disease (AWD) due to local recurrence or tumour progression (14 metastases, 5 low-grade malignant bone tumours, 4 Giant Cell Tumours). Eight patients died due to the disease (6 metastases, 2 osteosarcomas), while 1 died from leukaemia. One-hundred-and-eleven patients (78%) were classified as Continues Disease Free (CDF). All patients reported decrease in pain-related symptoms after surgery and all surgeons reported better control of blood loss. Three cases (2%) of local skin necrosis or wound dehiscence were reported. No local recurrences were reported after fibromatosis ablation. Our results confirm that CA could be considered as a safe and effective technique to treat various conditions as adjuvant and palliative therapy. In particular, in open surgery, cryotherapy as an adjuvant treatment could lead to very low rates of recurrence in locally aggressive tumours like Giant Cell Tumours. These results could be generalized but a better understanding about indications and outcomes can be reached studying CA in specific populations with comparation to other adjuvant techniques.

Life is precious: Sarcoma/giant-cell tumors survivors' perspectives on their psychological journey.

OBJECTIVES: Although surviving bone resection/limb salvage surgery treatment is the beginning of the journey towards recovery, the importance of providing patients with post-operative psychological support is often overlooked by health professionals. Hence, patients typically are left to their own devices in terms of ensuring their mental health and well-being. Methodological Approach and Participants: This qualitative analysis of seven long-term sarcoma survivors' reflective journal entries provides insights into the different phases of distress, resilience building, resilient growth and advice-giving that they moved through during their survivorship journey. INTERPRETATION: Our findings identify the fragility of patient resilience and highlight areas for future research.

Isolated limb perfusion as a treatment option for rare types of tumours.

BACKGROUND: Isolated limb perfusion (ILP) is an established and effective treatment for advanced melanoma and soft tissue sarcomas of the extremities with a high overall response rate. The aim of this study was to describe our experience of ILP for more rare types of tumours. METHODS: Patients with Merkel cell carcinoma (MCC) (n = 4), squamous cell carcinoma (SCC) (n = 2), B-cell lymphoma (n = 1), desmoid tumours (n = 3), pigmented villonodular synovitis (PVNS) (n = 1) and giant cell tumour (n = 1) were treated with ILP and analysed retrospectively. RESULTS: The four patients with in-transit MCC had three complete responses (CR) and one partial response (PR); the two patients with SCC had one CR and one stable disease (SD); the patients with desmoid tumours had two PR and one SD. A CR was also observed for the patient with a giant cell tumour, but the patient with PVNS had a SD. The patient with cutaneous metastases of B-cell lymphoma showed a CR, however with rapid systemic progression. Local toxicity according to Wieberdink was grade II in 10 patients (83%) and grade III in two patients (17%). CONCLUSIONS: These results show that ILP can be used as a treatment option also for more rare disease entities when other treatments have failed.

Treatment options and prognosis for repeatedly recurrent giant cell tumor of the spine.

BACKGROUND: Giant cell tumor of the spine has high rate of postoperative recurrence. There are not much published studies on repeatedly recurrent GCTS (RRGCTS). Also, there are controversies as to the prognostic factors and treatment options for RRGCTS. METHODS AND MATERIALS: A retrospective survival analysis between 2000 and September 2014 was performed on the 74 times of in-hospital treatment of the 21 patients. Recurrence-free survival was defined as the time between the date of surgery and the date of recurrence. Factors with P values <0.05 in univariate analysis were subjected to multivariate analysis by means of proportional hazard analysis. RESULT: A total of 21 patients comprising ten males and 11 females with a mean age of 29.7 years (range 15-49) were included, with a total of 74 times of surgery performed. Eighteen patients had no evidence of disease. Univariate and multivariate analysis suggested that total spondylectomy and bisphosphonate therapy were independent prognostic factors for better RFS in RRGCTS patients. CONCLUSION: Patients of RRGCTS are suitable for further surgical treatment with relatively good healing process and restoration of nervous function. Early diagnosis of recurrence may be associated with better prognosis. Total spondylectomy in combination with bisphosphonate therapy could reduce postoperative recurrence rate.

Clinical evaluation and management of benign soft tissue tumors of the extremities.

Benign lesions comprise a majority of soft tissue tumors. It has been estimated that their incidence outnumbers that of malignant tumors by a factor of at least 100 [1]. While history and physical examination can start the diagnostic process, imaging including the use of magnetic resonance imaging can be more helpful. Biopsy of these tumors is sometimes necessary and can be performed in a number of ways, often in conjunction with definitive treatment. Specific diagnostic and treatment strategies for a number of the more commonly encountered benign soft tissue tumors including lipomas, pigmented villonodular synovitis and hemangiomas are reviewed. An algorithm for the management of benign soft tissue tumors is discussed.

Giant cell tumors of the skull: a series of 18 cases and review of the literature.

Giant cell tumors (GCTs) are generally benign, locally aggressive lesions mostly located in the metaphysis of long bones. GCTs of the skull are rare and the majority of the cases have been presented as case reports. The authors retrospectively reported 18 patients with GCTs of the skull at a single institution from April 1994 to February 2012 and summarized the clinical, radiological, pathological characteristics and management of the disease. Meanwhile, a systematic review of 94 case reports of GCTs of the skull was performed. Headache and symptoms related to the involvement of intracranial nerves were the most common symptoms. Over 90 % of the tumors originated from sphenoid and temporal bones. On MRI, very low signal on T2-weighted images were found highly indicative of GCTs of the temporal bone. Univariate analysis revealed that extent of tumor resection and post-operative radiation therapy (RT) were prognostic factors significantly influencing the survival of the patients. We concluded that complete tumor resection is the optimal goal in treating this disease and adjuvant RT should be given once tumor residual is inevitable.

A multidisciplinary approach to giant cell tumors of tendon sheath and synovium--a critical appraisal of literature and treatment proposal.

Giant cell tumors deriving from synovium are classified into a localized (GCT of tendon sheath; GCT-TS) and diffuse form (diffuse-type GCT, Dt-GCT). We propose a multidisciplinary management based upon a systematic review and authors' opinion. Open excision for GCT-TS and open synovectomy (plus excision) for Dt-GCT is advised to reduce the relatively high recurrence risk. External beam radiotherapy should be considered in severe cases, as Dt-GCT commonly extends extra-articular.

Treatment of tenosynovial giant cell tumor and pigmented villonodular synovitis.

PURPOSE OF REVIEW: To review recent developments in the molecular pathogenesis of tenosynovial giant cell tumor (TGCT) or pigmented villonodular synovitis (PVNS) and its therapeutic implications. RECENT FINDINGS: TGCT or PVNS is a benign clonal neoplastic proliferation arising from the synovium characterized by a minor population of intratumoral cells that harbor a recurrent translocation. These cells overexpress CSF1, resulting in recruitment of CSF1R-bearing macrophages that are polyclonal and make up the bulk of the tumor. Inhibition of CSF1R using small molecule inhibitors such as imatinib, nilotinib or sunitinib can result in clinical, radiological and functional improvement in the affected joint. SUMMARY: Currently, surgery remains the treatment of choice for patients with TGCT/PVNS. Localized TGCT/PVNS is managed by marginal excision. Recurrences occur in 8-20% of patients and are easily managed by re-excision. Diffuse TGCT/PVNS tends to recur more often (33-50%) and has a much more aggressive clinical course. Patients are often symptomatic and require multiple surgical procedures during their lifetime. For patients with unresectable disease or multiple recurrences, systemic therapy using CSF1R inhibitors may help delay or avoid surgical procedures and improve functional outcomes.

A single-center experience with giant cell tumors of sphenoid bone and clivus.

OBJECTIVE: To present pathologic, clinical, and treatment findings for giant cell tumors (GCTs) of sphenoid bone and clivus. METHODS: We describe the optimal treatment algorithm in patients with a histopathologic diagnosis of bone GCT by presenting the effects of denosumab treatment in both pediatric and adult patients with GCT undergoing endoscopic transnasal surgery. Clinicopathologic correlation is crucial for the differential diagnosis of GCT and the choice of treatment modality. CONCLUSION: GCT of bone is a local aggressive tumor that accounts for about 3%-7% of all bone tumors. GCTs located in the cranium are extremely uncommon neoplasms. There are no defined guidelines for the treatment of GCTs in skull base. Following surgical resection of the tumor, the addition of denosumab treatments to radiotherapy has a significant role in preventing the recurrence of GCT and in promoting regression of residual tumor size.

The Efficacy of Radiofrequency Ablation for Bone Tumors Unsuitable for Radical Excision.

BACKGROUND: Bone tumors can cause severe pain and poor quality of life due to recurrence and non-achievement of complete remission after surgery, chemotherapy, or radiotherapy. Radiofrequency ablation (RFA) can be considered for minimally invasive treatment of bone tumors that are difficult to radically excise. In this study, RFA was performed for bone tumors that were difficult to radically excise and did not respond to surgery, chemotherapy, or radiotherapy due to their large sizes and/or locations. The purpose of this study was to retrospectively analyze the clinical characteristics and survival rates of bone tumors after RFA and provide one more treatment option for the future. METHODS: There were 43 patients with bone tumors who underwent percutaneous RFA at our hospital from April 2007 to October 2017. The median age of the patients was 59 years (range, 31-75 years), and the median follow-up duration was 67.2 months (range, 10.2-130.5 months). Of the 43 patients, 26 were male and 17 were female. Thirty-four cases were metastatic bone tumors, 5 were chordomas, 3 were osteosarcomas, and 1 was a giant cell tumor. Pain and functional ability of the patients were evaluated using a visual analog scale (VAS) and the Musculoskeletal Tumor Society (MSTS) functional scoring system, respectively. Scores were recorded preoperatively, 1 week postoperatively, and 4 weeks postoperatively. The 1-year, 2-year, and 5-year survival rates were evaluated using the Kaplan-Meier method. RESULTS: The mean VAS score was 8.21 preoperatively. The mean VAS score at 1 week, 4 weeks, 12 weeks, and 24 weeks postoperatively were 3.91, 3.67, 3.31, and 3.12, respectively. The mean preoperative MSTS score was 64.0% (range, 32%-87%). The mean postoperative MSTS score was 71.0% (range, 40%-90%). The 1-year, 2-year, and 5-year survival rates were 95.3%, 69.8%, and 30.2%, respectively. CONCLUSIONS: As per our study findings, RFA was effective in reducing pain and improving functional ability of patients with bone tumors that were difficult to radically excise.

Multidisciplinary management of primary tumors of the vertebral column.

OPINION STATEMENT: Primary spinal neoplasms are rare tumors that can lead to significant morbidity secondary to local bone destruction and invasion into adjacent neurological and vascular structures. These tumors represent a clinical challenge to even the most experienced physicians and require a multidisciplinary approach to ensure optimal patient outcomes. This review will discuss the most common primary bone tumors and focus on recent surgical, medical, and radiation treatment advances.

Giant cell tumour and central giant cell reparative granuloma of the skull: do these represent ends of a spectrum? A case report and literature review.

Giant cell tumour (GCT) of bone is an uncommon primary bone neoplasm typically occurring at the epiphyses of long bones in young adults. They are osteolytic neoplasms with approximate local recurrence rates of 25%, and 2% of patients develop pulmonary metastases. These tumours appear very rarely in the skull, with those few reported cases arising predominantly in the sphenoid and occasionally the temporal bones. They demonstrate benign histological features, but are locally aggressive and surgical excision is the treatment of choice. It is widely believed that giant cell tumours should be distinguished from other giant cell lesions, importantly central giant cell reparative granulomata (CGCG) which are thought to have a lower recurrence rate and for which no cases of malignant transformation or metastases have been reported. Investigators have noted that giant cell lesions in the skull bones may be unique and that GCT and CGCG may be part of a spectrum of a single disease process. We present a case of a giant cell tumour of the temporal bone which illustrates and re-emphasises this concept and review the literature on these lesions.

Endovascular embolization of a recurrent cervical giant cell neoplasm using N-butyl 2-cyanoacrylate.

Pre-operative endovascular embolization of spinal giant cell tumors (GCTs) has been an effective strategy to reduce blood loss during surgical resection. Traditionally, spinal GCTs have been embolized with polyvinyl acetate (PVA) particles. We present the pre-operative embolization of a recurrent cervical GCT with N-butyl 2-cyanoacrylate (NBCA) rather than PVA. The patient was a 17-year-old female who, 3 months prior, had undergone a surgical resection of a cervical GCT without pre-operative embolization. She returned with tumor recurrence in the approximate location. Resection was recommended, and pre-operative embolization was requested. The tumor was embolized with NBCA. Post-embolization angiography demonstrated significantly decreased tumor "blush" and a significant reduction of the vascular supply. This is the first reported use of NBCA for the pre-operative embolization of a cervical GCT. The benefits of NBCA over PVA particles include superior penetration, permanent tumor embolization and lower exposure to radiation due to shorter procedure time.

Recurrent and refractory giant cell tumor of the jaw.

Recurrent giant cell tumors refractory to various treatment modalities are challenging dilemmas for the most experienced practitioner. We report a case of a multiply recurrent aggressive giant cell tumor diagnosed at 10 months of age with extensive involvement of the maxillae and mandibles unresponsive to multiple therapeutic modalities. The various treatments attempted in this patient including conventional therapies as well as the original use of bevacizumab (Avastin) are described.

A case of giant cell tumor of the tendon sheath in an elderly patient: diagnostic difficulties and therapeutic options.

Giant cell tumor of the tendon sheath (GCTTS) is a benign tumor with a high recurrence rate of up to 50%. The lesion may appear anywhere in the synovium; the nature of this tumor is still controversial, however recent data shows that tenosynovial giant cell tumors (TGCTs) could be clonal neoplastic tumors. Most lesions of GCTTS produce one or more discrete nodules, while the radiological features can include soft-tissue masses with or without bone destruction. In an effort to advance in the understanding of GCTTS pathogenesis, we decided broadly investigate the immunophenotypic profile, of a TGCT in a 69-year-old female patient.

Malignant diffuse-type tenosynovial giant cell tumors: a series of 7 cases comparing with 24 benign lesions with review of the literature.

BACKGROUND: Malignant diffuse-type tenosynovial giant cell tumor (D-TSGCT), an unusual sarcoma with concurrent or previous benign D-TSGCTs, poses challenges to diagnosis and prognostication. METHODS: We described the radiologic, clinicopathologic, and immunophenotypical findings of 5 primary and 2 metachronous malignant D-TSGCTs and reviewed published cases to better delineate their morphologic spectrum and behavior. Twenty-four benign D-TSGCTs were also statically compared to analyze the diagnostic values of various variables. RESULTS: The 7 malignant cases affected 4 females and 3 males aged 45 to 78 (mean, 60.9) years, which included 1 intraarticular and 6 extra-articular lesions. These tumors were 5 to 17 cm (mean, 9.4) and located within or near the large joints of extremities. Magnetic resonance imaging revealed expansile or infiltrative masses with frequent lobulation and heterogeneous signals. Histologically, areas of benign D-TSGCTs blended abruptly or gradually with frank sarcomas composed of pleomorphic, spindle, or enlarged oval cells, forming malignant fibrous histiocytomalike (n = 4), fibrosarcomatous (n = 1), myxosarcomatous (n = 1), or giant cell tumorlike (n = 1) patterns. One patient experienced recurrences twice, and another 3 developed metastases to the lymph nodes (n = 2), lung (n = 1), or vertebrae (n = 1), with 1 dying from disseminated diseases. An older age (P = 0.003), a larger size (P = 0.036), tumor necrosis (P < 0.001), atypical mitoses (P < 0.001), and Ki-67 overexpression (P < 0.001) appeared preferentially in malignant lesions, but these parameters had overlap between few benign and malignant tumors. CONCLUSIONS: Malignant D-TSGCTs are a distinct sarcoma with considerable morphologic variability, metastatic propensity, and lethality. Altered architecture with anaplastic cells represents an important distinguishing feature, while abnormalities of other parameters should not be directly equated with malignancy.