Girolami Ilaria, Mancini Irene, Simoni Antonella, Baldi Giacomo Giulio, Simi Lisa, Campanacci Domenico, Beltrami Giovanni, Scoccianti Guido, D'Arienzo Antonio, Capanna Rodolfo, Franchi Alessandro
Department of Surgery and Translational Medicine, University of Florence, Florence, Italy.
Department of Clinical and Experimental Biomedical Sciences, University of Florence, Florence, Italy.
J Clin Pathol. 2016 Mar;69(3):240-7. doi: 10.1136/jclinpath-2015-203248. Epub 2015 Sep 3.
Denosumab, a fully human monoclonal antibody directed against RANKL, has recently been introduced in the treatment strategy of giant cell tumour of bone (GCTB). Aim of this study was to investigate the phenotypical modifications induced by denosumab treatment in a series of 15 GCTB.
The tumours were characterised for histone 3.3 mutations, and studied immunohistochemically for the modifications of RANKL, RANK, SATB2 and RUNX2 expression, as well as of tumour proliferative activity and angiogenesis.
Nine of 11 tumours investigated presented a histone 3.3 mutation in H3F3A, and 2 of these for which the analysis was carried out in pretreatment and post-treatment specimens showed the same mutation in both. Denosumab induced the disappearance of osteoclast-like giant cells, leaving residual spindle neoplastic cells arranged in a storiform pattern, with deposition of trabecular collagen matrix and osteoid, which tended to maturation in the peripheral portions of the lesion. RANK and RANKL expression was variable, with no significant variation after treatment. Moreover, we did not observe any significant modification of the expression of the osteoblastic markers SATB2 and RUNX2. Denosumab treatment determined a significant reduction of the proliferative index and of tumour angiogenesis (p=0.001, Wilcoxon rank-sum test).
These results indicate that denosumab induces a partial maturation towards the osteoblastic phenotype of the neoplastic cells of GCTB, with production of fibrous and osteoid matrix, but with minor immunophenotypical changes. Finally, we first report an antiangiogenic activity of denosumab in GCTB, possibly mediated by a RANKL-dependent pathway.
地诺单抗是一种针对核因子κB受体活化因子配体（RANKL）的全人单克隆抗体，最近已被引入骨巨细胞瘤（GCTB）的治疗策略中。本研究的目的是调查地诺单抗治疗对15例GCTB所诱导的表型改变。
对肿瘤进行组蛋白3.3突变特征分析，并通过免疫组织化学研究RANKL、RANK、SATB2和RUNX2表达的改变，以及肿瘤增殖活性和血管生成情况。
在11例接受调查的肿瘤中，有9例在H3F3A基因存在组蛋白3.3突变，其中2例在治疗前和治疗后的标本中均进行了分析，两者显示相同的突变。地诺单抗导致破骨细胞样巨细胞消失，留下呈车辐状排列的残余梭形肿瘤细胞，伴有小梁胶原基质和类骨质沉积，这些在病变的周边部分趋于成熟。RANK和RANKL表达存在差异，治疗后无显著变化。此外，我们未观察到成骨细胞标志物SATB2和RUNX2表达有任何显著改变。地诺单抗治疗导致增殖指数和肿瘤血管生成显著降低（p = 0.001，Wilcoxon秩和检验）。
这些结果表明，地诺单抗诱导GCTB肿瘤细胞向成骨细胞表型部分成熟，伴有纤维和类骨质基质的产生，但免疫表型变化较小。最后，我们首次报道地诺单抗在GCTB中具有抗血管生成活性，可能由RANKL依赖性途径介导。
