Aberrant paracrine signalling for bone remodelling underlies the mutant histone-driven giant cell tumour of bone.

Oncohistones represent compelling evidence for a causative role of epigenetic perturbations in cancer. Giant cell tumours of bone (GCTs) are characterised by a mutated histone H3.3 as the sole genetic driver present in bone-forming osteoprogenitor cells but absent from abnormally large bone-resorbing osteoclasts which represent the hallmark of these neoplasms. While these striking features imply a pathogenic interaction between mesenchymal and myelomonocytic lineages during GCT development, the underlying mechanisms remain unknown. We show that the changes in the transcriptome and epigenome in the mesenchymal cells caused by the H3.3-G34W mutation contribute to increase osteoclast recruitment in part via reduced expression of the TGF-beta-like soluble factor, SCUBE3. In turn, osteoclasts secrete unregulated amounts of SEMA4D enhancing proliferation of mutated osteoprogenitors and arresting their maturation. These findings provide a mechanism by which GCTs undergo differentiation upon denosumab treatment, a drug that depletes osteoclasts. In contrast, gain of hTERT activity, commonly found in malignant GCT, makes neoplastic cells insensitive to osteoclasts, predicting the unresponsiveness to denosumab. We provide a mechanism for GCT initiation and its response to current treatment, the basis of which is dysfunctional cross-talk between bone-forming and bone-resorbing cells, emphasising the importance of tumor/microenvironment bidirectional interactions in tumorigenesis.

Limb salvage surgery for giant cell tumours around knee joint: a single institute experience

<p class="abstract"><strong>Background:</strong> Giant cell tumours (GCTs) of bone are benign but locally aggressive tumours. The surgical treatment of GCTs in the around knee joint mainly includes curettage and bone grafting, extended curettage and cement filling, segmental resection and modular endo prosthesis reconstruction.</p><p class="abstract"><strong>Methods:</strong> Retrospective analysis of the presentation, the functional outcome following modular endoprosthetic reconstruction, prosthetic survival and the recurrence rate in 17 patients with Campanacci grade 3 GCTs involving distal femur and proximal tibia, who underwent segmental resection and modular endoprosthesis reconstruction in a single centre from 2015 to 2018. The surgery was performed according to the general principles of limb salvage surgery and modular segmental replacement was used. All stems were cemented in place. Isometric exercises and mobilization with crutches were started on 2^nd postoperative day. Knee joint bending was started for proximal tibia patients after 2 to 3 weeks. Functional outcome was scored by musculoskeletal tumour society scoring (MSTS). Immediate post-operative complication like delayed wound healing, flap necrosis, wound infection, foot drop, leg length discrepancies were evaluated.<strong></strong></p><p class="abstract"><strong>Results:</strong> The average MSTS functional score was 78%.3 year prosthetic survival was 100%. None of the patients had recurrence. One patient had left lower lobe metastasis for which wedge resection was done.</p><p class="abstract"><strong>Conclusions:</strong> Segmental resection and endoprosthetic replacement has good functional outcome in patients with tumours around the knee joint. As GCTs are tumours with less chance of local and distant metastasis after complete excision, endoprosthetic prosthesis is a good treatment option after complete excision.</p>

‘Triple Clear’: A Systematic and Up-to-Date Surgical Process for Giant Cell Tumor of Bone Graded Companacci II and III with or without Pathological Fracture and Joint Invasion

Objectives: 1) To describe a systematic process for giant cell tumours of bone (GCTB). 2) To compare the clinical effects of ‘triple clear’ (TC) and segmental resection (SR), bone grafts and bone cement.Method: Patients with primary GCTB graded Companacci II and III who were treated with either SR (n = 39) or TC (n = 41) were included. The pain level was determined by the Visual Analogue Scale. Limb function was determined by the Musculoskeletal Tumour Society (MSTS) score.Result: The operating time was 135.7±38.4 min in the TC group and 174.2±43.0 min in the SR group (P<0.05). The recurrence rates were 7.3% and 10.0%, respectively (P = 0.37). The MSTS scores at three months after surgery were 19.8±1.5 in the TC group and 18.8±1.5 in the SR group. The MSTS scores at two years were 26.3±0.7 and 24.2±1.6, respectively (P＜0.05).Conclusion: TC is recommended for GCTB graded Companacci II-III and GCTB accompanied by pathological fracture or joint invasion. Bone grafts may be more suitable than bone cement in the long term.

Giant cell tumour of hand bones: outcomes of treatment

The purpose of this study was to report the incidence of giant cell tumour of the hand bones in an Asian population, document treatment options and report outcomes of treatment. Of 698 giant cell tumours of bone that underwent surgery between January 2011 and December 2020 at our institute, only 22 (3%) were in the hand. Fourteen occurred in the metacarpals, eight in the phalanges. Fifteen were primary tumours and seven had recurrent disease. Twenty lesions had an associated soft tissue component. Two patients treated for primary disease and one who had been treated for recurrence had local recurrence. Recurrence occurred in two of nine patients treated with curettage, one of three with resection and none of five with ray or digit amputation. Both curettage and resection/amputation are acceptable treatment options for the rare condition of giant cell tumour of bone in the hand, with a need to individualize treatment decisions based on the site and extent of disease to minimize treatment morbidity while maximizing disease control. Level of evidence: IV

Unusual Location of a Giant Cell Tumour

Giant cell tumours (GCT) are rare aggressive non-cancerous tumours which usually affect the long bones. We describe a case of GCT of the first rib in a young woman without a relevant history. The patient presented a left cervico-thoracic mass which was biopsied in our department (CT-guided biopsy). She was referred to the thoracic surgery department after histological results.

Diagnostic difficulty of an aggressive and recurrent giant cell granuloma: a short case report

Introduction: The central giant cell granuloma (CGCG) is a rare benign lesion of the jaws, rarely aggressive,mostly affecting the mandible in children and young adults. The diagnosis may be difficult, complementaryhistological analyses being necessary to differentiate it from other giant cell tumours. Observation: A 28-year-old woman consulted for a painful gingival swelling surrounding the inferior right second molar. Cone Beam (CBCT) showed anunilocular radiolucent mandibular lesion. Histological examination performed after the curettage of the lesion could not differentiate between a peripheral GCG with bone extension, a giant cell tumour (GCT) or a CGCG. The patient was lost of view for 4 months until an aggressive recurrence. Asegmental mandibulectomy in disease-free margin was performed. Immunohistochemical and genetic testscomplementary to histology finally permitted to concludeto a CGCG. The patient presented no recurrence in 4 years of follow-up. Discussion: Surgical removal in disease-free margin is the gold standard treatment in aggressive CGCG. Nonetheless, literature reports alternative pharmacological treatments alone or in addition to surgery. In this case, the aggressiveness of the tumour and the absence of patient compliance for follow-up have led to the decision of a radical treatment of the recurrence. Conclusion: Aggressive CGCG requires a rapid diagnosis and a primary disease-free margin surgical resection to avoid mutilating treatment of the recurrence.