Laboratory of Musculoskeletal Oncology, Center for Skeletal Disease and Tumor Metastasis, Van Andel Institute, Grand Rapids, Mich; Department of Orthopaedic Surgery, Grand Rapids Medical Education Partners, Grand Rapids, Mich.
Laboratory of Musculoskeletal Oncology, Center for Skeletal Disease and Tumor Metastasis, Van Andel Institute, Grand Rapids, Mich.
Transl Res. 2014 Aug;164(2):139-48. doi: 10.1016/j.trsl.2014.03.005. Epub 2014 Mar 21.
Aneurysmal bone cyst (ABC) is a benign tumor of bone presenting as a cystic, expansile lesion in both the axial and appendicular skeleton. Axial lesions demand special consideration, because treatment-related morbidity can be devastating. In similar lesions, such as giant cell tumor of bone (GCTB), the receptor-activator of nuclear kappaB ligand (RANKL)-receptor-activator of nuclear kappaB (RANK) signaling axis is essential to tumor progression. Although ABC and GCTB are distinct entities, they both contain abundant multinucleated giant cells and are osteolytic characteristically. We hypothesize that ABCs express both RANKL and RANK similarly in a cell-type specific manner, and that targeted RANKL therapy will mitigate ABC tumor progression. Cellular expression of RANKL and RANK was determined in freshly harvested ABC samples using laser confocal microscopy. A consistent cell-type-specific pattern was observed: fibroblastlike stromal cells expressed RANKL strongly whereas monocyte/macrophage precursor and multinucleated giant cells expressed RANK. Relative RANKL expression was determined by quantitative real-time polymerase chain reaction in ABC and GCTB tissue samples; no difference in relative expression was observed (P > 0.05). In addition, we review the case of a 5-year-old boy with a large, aggressive sacral ABC. After 3 months of targeted RANKL inhibition with denosumab, magnetic resonance imaging demonstrated tumor shrinkage, bone reconstitution, and healing of a pathologic fracture. Ambulation, and bowel and bladder function were restored at 6 months. Denosumab treatment was well tolerated. Post hoc analysis demonstrated strong RANKL expression in the pretreatment tumor sample. These findings demonstrate that RANKL-RANK signal activation is essential to ABC tumor progression. RANKL-targeted therapy may be an effective alternative to surgery in select ABC presentations.
骨巨细胞瘤（ABC）是一种良性骨肿瘤，表现为轴骨和附肢骨骼的囊性、膨胀性病变。轴骨病变需要特别考虑，因为治疗相关的发病率可能是毁灭性的。在类似的病变中，如骨巨细胞瘤（GCTB），核因子 kappaB 配体（RANKL）-核因子 kappaB 受体（RANK）信号轴对于肿瘤的进展是必不可少的。尽管 ABC 和 GCTB 是不同的实体，但它们都含有丰富的多核巨细胞，并且具有典型的溶骨性。我们假设 ABC 以细胞类型特异性的方式表达 RANKL 和 RANK，并且靶向 RANKL 治疗将减轻 ABC 肿瘤的进展。使用激光共聚焦显微镜在新鲜采集的 ABC 样本中确定 RANKL 和 RANK 的细胞表达。观察到一致的细胞类型特异性模式：成纤维细胞样基质细胞强烈表达 RANKL，而单核/巨噬细胞前体和多核巨细胞表达 RANK。通过定量实时聚合酶链反应在 ABC 和 GCTB 组织样本中确定 RANKL 的相对表达；未观察到相对表达的差异（P > 0.05）。此外，我们回顾了一名 5 岁男孩患有大型侵袭性骶骨 ABC 的病例。在使用地舒单抗进行 3 个月的靶向 RANKL 抑制后，磁共振成像显示肿瘤缩小、骨重建和病理性骨折愈合。在 6 个月时恢复了活动能力以及肠和膀胱功能。地舒单抗治疗耐受良好。事后分析显示，预处理肿瘤样本中存在强烈的 RANKL 表达。这些发现表明 RANKL-RANK 信号激活对于 ABC 肿瘤的进展至关重要。RANKL 靶向治疗可能是某些 ABC 表现的手术替代方案。
