Department of Biopathology, Institut Bergonié, Comprehensive Cancer Center, Bordeaux, France.
Bordeaux Institute of Oncology, BRIC, INSERM, Bordeaux University, Bergonié Institute, Bordeaux, France.
Am J Surg Pathol. 2023 Jul 1;47(7):801-811. doi: 10.1097/PAS.0000000000002051. Epub 2023 May 12.
Giant cell tumors (GCTs) with high mobility group AT-Hook 2 ( HMGA2 )::nuclear receptor corepressor 2 ( NCOR2 ) fusion are rare mesenchymal tumors of controversial nosology, which have been anecdotally reported to respond to CSFR1 inhibitors. Here, we performed a comprehensive study of 6 GCTs with HMGA2::NCOR2 fusion and explored their relationship with other giant cell-rich neoplasms. Tumors occurred in 4 females and 2 males ranging in age from 17 to 32 years old (median 24). Three lesions originated in subcutaneous soft tissue and 3 in bone. Tumor size ranged from 20 to 33 mm (median 27 mm). The lesions had a nodular/multinodular architecture and were composed of sheets of mononuclear "histiocytoid" cells with uniform nuclei intermingled with multinucleated giant cells. Mitotic activity was low and nuclear atypia and metaplastic bone were absent. Variable findings included necrosis, cystic degeneration, lymphocytic infiltrate (sometimes forming nodules), and xanthogranulomatous inflammation. On immunohistochemistry, all cases focally expressed pan-keratin and were negative with SATB2 and H3.3G34W. Whole RNA-sequencing was performed in all cases of GCT with HMGA2::NCOR2 fusion and a subset of giant cell-rich tumors (tenosynovial-GCT, n = 19 and "wild-type" GCT of soft tissue, n = 9). Hierarchical clustering of RNA-sequencing data showed that GCT with HMGA2::NCOR2 fusion formed a single cluster, independent of the other 2 entities. Methylome profiling showed similar results, but the distinction from "wild-type" GCT of soft tissue was less flagrant. Gene expression analysis showed similar levels of expression of the CSF1/CSFR1 axis between GCT with HMGA2::NCOR2 fusion and tenosynovial-GCT, supporting their potential sensitivity to CSFR1 inhibitors. Clinical follow-up was available for 5 patients (range: 10 to 64 mo; median 32 mo). Three patients (60%) experienced local recurrences, whereas none had distant metastases or died of disease. Overall, our study confirms and expands previous knowledge on GCT with HMGA2::NCOR2 fusion and supports its inclusion as an independent entity.
高迁移率族蛋白 A2（HMGA2）-核受体共抑制因子 2（NCOR2）融合的巨细胞瘤（GCTs）是一种罕见的具有争议性分类学的间叶性肿瘤，据报道，其对细胞因子受体 1（CSF1R）抑制剂有反应。在这里，我们对 6 例 HMGA2::NCOR2 融合的 GCT 进行了全面研究，并探讨了它们与其他富含巨细胞的肿瘤之间的关系。肿瘤发生于 4 名女性和 2 名男性，年龄 17-32 岁（中位年龄 24 岁）。3 个病变起源于皮下软组织，3 个起源于骨。肿瘤大小为 20-33mm（中位 27mm）。病变具有结节/多结节结构，由均匀核的单核“组织细胞样”细胞片层与多核巨细胞混合而成。有丝分裂活性低，无核异型性和骨改建。可变的发现包括坏死、囊性变性、淋巴细胞浸润（有时形成结节）和黄色肉芽肿性炎症。免疫组织化学染色显示，所有病例均局灶性表达泛角蛋白，SATB2 和 H3.3G34W 阴性。所有 HMGA2::NCOR2 融合的 GCT 和一部分富含巨细胞的肿瘤（腱鞘巨细胞瘤，n=19 和“野生型”软组织 GCT，n=9）均进行了全 RNA 测序。RNA 测序数据的层次聚类显示，HMGA2::NCOR2 融合的 GCT 形成了一个单独的簇，与其他 2 个实体无关。甲基组谱分析也得到了类似的结果，但与“野生型”软组织 GCT 的区别不那么明显。基因表达分析显示，HMGA2::NCOR2 融合的 GCT 与腱鞘巨细胞瘤之间 CSF1/CSF1R 轴的表达水平相似，支持它们对 CSF1R 抑制剂的潜在敏感性。5 例患者（10-64 个月，中位 32 个月）有临床随访资料。3 例（60%）患者局部复发，无远处转移或死于疾病。总之，我们的研究证实并扩展了以前关于 HMGA2::NCOR2 融合的 GCT 的知识，并支持将其作为一个独立的实体纳入。
