Diagnostic utility of histone H3.3 G34W, G34R, and G34V mutant-specific antibodies for giant cell tumors of bone
Diagnostic utility of histone H3.3 G34W, G34R, and G34V mutant-specific antibodies for giant cell tumors of bone
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DOI：
10.1016/j.humpath.2017.11.020
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发表时间：
2018-03-01
期刊：
影响因子：
3.3
通讯作者：
Oda, Yoshinao
中科院分区：
文献类型：
--
作者：
Yamamoto, Hidetaka;Iwasaki, Takeshi;Oda, Yoshinao
骨巨细胞瘤（GCTB）的特点是单核基质细胞和破骨细胞样巨细胞；高达95%的人有H3F3A基因突变。 RANKL 抑制剂地诺塞麦用于治疗 GCTB 时，会导致组织学变化，例如新骨形成和巨细胞耗竭。在这里，我们评估了使用抗组蛋白 H3.3 G34W、G34R 和 G34V 突变蛋白的抗体进行免疫组织化学染色对 GCTB 和其他组织学相似的骨和关节病变的诊断效用。 H3.3 在原发性 GCTB 病例中，分别有 47/51 (92%)、1/51 (2%) 和 3/51 (6%) 病例的单核基质细胞中检测到 G34W、G34R 和 G34V 表达，且呈相互排斥的方式。所有复发/转移性 GCTB (n = 14)、地诺单抗治疗后 GCTB (n = 8) 和继发性恶性 GCTB (n = 2) 均为 H3.3 G34W 阳性。免疫组化结果与突变分析确定的H3F3A基因型基本相关。在狄诺塞麦治疗后的 GCTB 中，未成熟的骨形成细胞中观察到 H3.3 G34W 表达。 H3.3 121/122例非GCTB中G34W、G34R和G34V阴性，包括软骨母细胞瘤、骨肉瘤、原发性动脉瘤性骨囊肿等富含巨细胞的病变。例外的是一例未分化的高级别多形性肉瘤，其 H3.3 G34W 呈阳性，提示原发性恶性 GCTB 肉瘤过度生长的可能性。因此，H3.3 G34W/R/V突变体特异性抗体是H3F3A基因型的有用替代标记，有助于GCTB及其变异体的诊断。 H3.3 G34W 突变蛋白在地诺单抗治疗后 GCTB 中的表达表明肿瘤基质细胞可能在新骨形成中发挥作用。 (C) 2017 Elsevier Inc. 保留所有权利。
Giant cell tumors of bone (GCTBs) are characterized by mononuclear stromal cells and osteoclast-like giant cells; up to 95% have H3F3A gene mutation. The RANKL inhibitor denosumab, when used for the treatment of GCTB, leads to histological changes such as new bone formation and giant cell depletion. Here we assessed the diagnostic utility of immunohistochemical staining with the antibodies against histone H3.3 G34W, G34R and G34V mutant proteins for GCTB and other histologically similar bone and joint lesions. H3.3 G34W, G34R and G34V expressions were detected in mononuclear stromal cells in 47/51 (92%), 1/51 (2%) and 3/51 (6%) cases of primary GCTBs, respectively, in a mutually exclusive manner. All recurrent/metastatic GCTBs (n = 14), post-denosumab GCTBs (n = 8) and secondary malignant GCTBs (n = 2) were positive for H3.3 G34W. The immunohistochemical results were essentially correlated with the H3F3A genotype determined by mutation analysis. In post-denosumab GCTBs, H3.3 G34W expression was seen in immature bone-forming cells. H3.3 G34W, G34R and G34V were negative in 121/122 cases of non-GCTB, including chondroblastoma, osteosarcoma, primary aneurysmal bone cyst and other giant cell rich lesions. The exception was a single case of undifferentiated high-grade pleomorphic sarcoma that was positive for H3.3 G34W, suggesting the possibility of sarcomatous overgrowth of primary malignant GCTB. Therefore, H3.3 G34W/R/V mutant-specific antibodies are useful surrogate markers for the H3F3A genotype and helpful for the diagnosis of GCTB and its variants. The expression of H3.3 G34W mutant protein in post-denosumab GCTB suggests that neoplastic stromal cells may play a role in new bone formation. (C) 2017 Elsevier Inc. All rights reserved.