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Late Local Recurrence of Bone Giant Cell Tumors Associated with an Increased Risk for Malignant Transformation.

ABSTRACT: In giant cell tumor of bone (GCTB), an intermediate malignant bone tumor, approximately 4% of all cases undergo malignant transformation. Accordingly, we analyzed risk factors for malignant transformation of GCTB treated without radiotherapy. We retrospectively reviewed medical records of 530 patients with GCTB of the extremities, admitted and treated at two institutions between January 1980 and December 2019. Overall, 4 patients with primary malignant GCTB, 4 patients with missing data, 3 patients with a history of radiotherapy, 22 patients with a follow-up of less than 6 months, and 36 patients who received denosumab were excluded. Accordingly, 461 patients were included for further analysis. Malignant transformation was observed in 15 of 461 patients (3.3%) at a median follow-up period of 192 months. The median follow-up duration was 89.4 months. Multivariate analysis revealed that local recurrence was an independent prognostic factor for unfavorable malignant transformation (Hazard ratio [HR], 11.33; 95% confidence interval [CI] 2.33-55.13; p = 0.003 for once versus none and HR, 11.24; 95% CI, 1.76-71.96; and p = 0.011 for twice or more versus none). The interval between the last surgery to local recurrence and malignant transformation was longer than that to local recurrence of benign GCTB, with a median of 15.2 years (interquartile range [IQR], 5.2-25.4) versus 1.3 months (IQR, 0.8-2.6), respectively (p < 0.001). Late local recurrence of GCTB is associated with a higher risk of malignant transformation.

SUBMITTER: Tsukamoto S

PROVIDER: S-EPMC8304778 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The rare benign giant cell tumour of bone (GCTB) is defined by an almost unique mutation in the H3.3 family of histone genes H3-3A or H3-3B; however, the same mutation is occasionally found in primary malignant bone tumours which share many features with the benign variant. Moreover, lung metastases can occur despite the absence of malignant histological features in either the primary or metastatic lesions. Herein we investigated the genetic events of 17 GCTBs including benign and malignant variants and the methylation profiles of 122 bone tumour samples including GCTBs. Benign GCTBs possessed few somatic alterations and no other known drivers besides the H3.3 mutation, whereas all malignant tumours harboured at least one additional driver mutation and exhibited genomic features resembling osteosarcomas, including high mutational burden, additional driver event(s), and a high degree of aneuploidy. The H3.3 mutation was found to predate the development of aneuploidy. In contrast to osteosarcomas, malignant H3.3-mutated tumours were enriched for a variety of alterations involving TERT, other than amplification, suggesting telomere dysfunction in the transformation of benign to malignant GCTB. DNA sequencing of the benign metastasising GCTB revealed no additional driver alterations; polyclonal seeding in the lung was identified, implying that the metastatic lesions represent an embolic event. Unsupervised clustering of DNA methylation profiles revealed that malignant H3.3-mutated tumours are distinct from their benign counterpart, and other bone tumours. Differential methylation analysis identified CCND1, encoding cyclin D1, as a plausible cancer driver gene in these tumours because hypermethylation of the CCND1 promoter was specific for GCTBs. We report here the genomic and methylation patterns underlying the rare clinical phenomena of benign metastasising and malignant transformation of GCTB and show how the combination of genomic and epigenomic findings could potentially distinguish benign from malignant GCTBs, thereby predicting aggressive behaviour in challenging diagnostic cases. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Project description:BackgroundFollowing curettage of giant cell tumor of bone (GCTB), it is common to fill the cavity with polymethylmethacrylate (PMMA) bone cement, bone allograft, or artificial bone to maintain bone strength; however, there is a 2-14% risk of postoperative fractures. We conducted this retrospective study to clarify the risk factors for fractures after curettage for GCTB of the extremities.MethodsThis study included 284 patients with GCTBs of the extremities who underwent curettage at our institutions between 1980 and 2018 after excluding patients whose cavities were not filled with anything or who had additional plate fixation. The tumor cavity was filled with PMMA bone cement alone (n = 124), PMMA bone cement and bone allograft (n = 81), bone allograft alone (n = 63), or hydroxyapatite graft alone (n = 16).ResultsFractures after curettage occurred in 10 (3.5%) patients, and the median time from the curettage to fracture was 3.5 months (interquartile range [IQR], 1.8-8.3 months). The median postoperative follow-up period was 86.5 months (IQR, 50.3-118.8 months). On univariate analysis, patients who had GCTB of the proximal or distal femur (1-year fracture-free survival, 92.5%; 95% confidence interval [CI]: 85.8-96.2) presented a higher risk for postoperative fracture than those who had GCTB at another site (100%; p = 0.0005). Patients with a pathological fracture at presentation (1-year fracture-free survival, 88.2%; 95% CI: 63.2-97.0) presented a higher risk for postoperative fracture than those without a pathological fracture at presentation (97.8%; 95% CI: 95.1-99.0; p = 0.048). Patients who received bone grafting (1-year fracture-free survival, 99.4%; 95% CI: 95.7-99.9) had a lower risk of postoperative fracture than those who did not receive bone grafting (94.4%; 95% CI: 88.7-97.3; p = 0.003).ConclusionsFor GCTBs of the femur, especially those with pathological fracture at presentation, bone grafting after curettage is recommended to reduce the risk of postoperative fracture. Additional plate fixation should be considered when curettage and cement filling without bone grafting are performed in patients with GCTB of the femur. This should be specially performed for those patients with a pathological fracture at presentation.

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Late Local Recurrence of Bone Giant Cell Tumors Associated with an Increased Risk for Malignant Transformation.

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