婴儿型纤维肉瘤5例靶向治疗的临床病理特征与分子遗传学分析

Targeted therapy of infantile fibrosarcoma:a clinicopathological and molecular genetic analysis of 5 cases

目的 探讨靶向治疗的婴儿型纤维肉瘤(infantile fibrosarcoma, IFS)的临床病理学、免疫表型和分子遗传学特征。方法 收集5例靶向治疗的IFS临床资料,采用免疫组化EnVision两步法检测pan-TRK、NGF、NT3和BDNF等的表达,应用FISH法和NGS技术检测NTRK基因,分析其临床病理特征与TRK抑制剂治疗的预后情况,并复习相关文献。结果 镜下3例IFS可见梭形肿瘤细胞呈交织束状或鱼骨样排列,1例IFS可见较原始的小圆形肿瘤细胞,1例IFS可见血管外皮瘤样结构。免疫表型:3例肿瘤细胞pan-TRK阳性,2例灶阳性;1例NGF强阳性,NT3和BDNF均阴性。分子病理:5例IFS使用NTRK1/2/3分离探针行FISH检测均显示NTRK基因断裂,通过ETV6分离探针和RNA-seq二代测序进一步验证,证实4例ETV6-NTRK3融合和1例LMNA1-NTRK1融合。患者活检/完整切除术后均使用TRK抑制剂治疗,其中1例肿瘤缩小后进行切除,未见肿瘤细胞,NTRK基因融合消失。患者随访时间27~62个月,预后均良好。结论 NTRK基因融合是IFS的分子特征,TRK是NTRK基因融合的IFS治疗重要靶点,TRK抑制剂具有较高的有效性和安全性。

Purpose To investigate the clinicopathological features,immunophenotypic and molecular genetic characteristics infantile fibrosarcoma(IFS)with targeted therapy.Methods Clinical data of 5 cases of IFS treated with targeted therapy were collected.Immunohistochemistry EnVision two-step method was used to analyze the expression of pan-TRK,NGF,NT3 and BDNF.FISH method and NGS was used to detect the NTRK gene.Its clinical pathological characteristics and the prognosis after TRK inhibitor treatment were analyzed,and relevant literatures were reviewed.Results Microscopically,3 cases showed spindle tumor cells arranged in an interwoven bundle or fishbone like pattern,1 case was mostly primitive round tumor cells,and 1 case had hemangiopericytoma-like pattern.Immunohistochemistry showed diffuse expression of pan TRK in 3 cases and focal expression in 2 cases.NGF was strongly expressed in 1 case,NT3 and BDNF was negative.FISH detection using NTRK1/2/3 split probe in 5 cases of IFS showed NTRK gene breakage.Further verification by EVT6 split probe and RNA-seq next-generation sequencing confirmed ETV6-NTRK3 fusion in 4 cases and LMNA1-NTRK1 fusion in 1 case.After biopsy/complete resection,all patients were treated with TRK inhibitors.One case underwent tumor reduction and resection tumor cells disappearance,and NTRK gene fusion disappeared.The follow-up period was 27-62 months,and the prognosis of the patients was good.Conclusion NTRK gene fusion is a molecular feature of IFS,and TRK is an important therapeutic target for IFS patients with NTRK gene fusion.TRK inhibitors have high efficacy and safety.