Abstract：
Alterations in kinase genes such as NTRK1/2/3, RET, and BRAF underlie infantile fibrosarcoma (IFS), the emerging entity \'NTRK-rearranged spindle cell neoplasms\' included in the latest WHO classification, and a growing set of tumors with overlapping clinical and pathological features. In this study, we conducted a comprehensive clinicopathological and molecular analysis of 22 cases of IFS and other kinase gene-altered spindle cell neoplasms affecting both pediatric and adult patients. Follow-up periods for 16 patients ranged in length from 10 to 130 months (mean 38 months). Six patients were treated with targeted therapy, achieving a partial or complete response in five cases. Overall, three cases recurred and one metastasized. Eight patients were free of disease, five were alive with disease, and two patients died. All cases showed previously reported morphological patterns. Based on the cellularity and level of atypia, cases were divided into three morphological grade groups. S100 protein and CD34 were at least focally positive in 12/22 and 14/22 cases, respectively. Novel PWWP2A::RET, NUMA1::RET, ITSN1::RAF1, and CAPZA2::MET fusions, which we report herein in mesenchymal tumors for the first time, were detected by RNA sequencing. Additionally, the first uterine case with BRAF and EGFR mutations and CD34 and S100 co-expression is described. DNA sequencing performed in 13 cases uncovered very rare additional genetic aberrations. The CNV profiles showed that high-grade tumors demonstrate a significantly higher percentage of copy number gains and losses across the genome compared with low- and intermediate-grade tumors. Unsupervised clustering of the tumors\' methylation profiles revealed that in 8/9 cases, the methylation profiles clustered with the IFS methylation class, irrespective of their clinicopathological or molecular features. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
摘要：
激酶基因的变化，如NTRK1/2/3，RET，BRAF是婴儿纤维肉瘤（IFS）的基础，WHO最新分类中包括的新兴实体“NTRK重排的梭形细胞肿瘤”，以及越来越多的临床和病理特征重叠的肿瘤。在这项研究中,我们对22例影响儿童和成人患者的IFS和其他激酶基因改变的梭形细胞肿瘤进行了全面的临床病理和分子分析。16例患者的随访期为10至130个月（平均38个月）。6例患者接受靶向治疗，在五种情况下实现部分或完全反应。总的来说,3例复发，1例转移。八名患者没有疾病，五个人带着疾病活着，两个病人死了.所有病例均显示先前报道的形态模式。根据细胞的数量和非典型性水平，病例分为三个形态学等级组。在12/22和14/22例中，S100蛋白和CD34至少为局灶性阳性。分别。新型PWWP2A::RET，NUMA1::RET,ITSN1::RAF1和CAPZA2::MET融合，我们在这里首次报道了间质肿瘤，通过RNA测序检测。此外,描述了首例BRAF和EGFR突变且CD34和S100共表达的子宫病例.在13例病例中进行的DNA测序发现了非常罕见的其他遗传畸变。CNV谱显示，与低级和中级肿瘤相比，高级肿瘤在整个基因组中显示出明显更高的拷贝数增加和丢失百分比。肿瘤甲基化谱的无监督聚类显示，在8/9例病例中，甲基化谱与IFS甲基化类别聚集在一起，无论其临床病理或分子特征。©2024作者由JohnWiley＆SonsLtd代表英国和爱尔兰病理学会出版的病理学杂志。
