RET基因融合阳性非小细胞肺癌患者的临床病理学特征

Clinicopathological features of patients with RET fusion-positive non-small cell lung cancer

目的探讨RET基因融合阳性非小细胞肺癌患者的临床病理学特征及治疗与预后。方法选取2018年8月至2020年4月江南大学附属医院存档的非小细胞肺癌标本1089例,采用多种基因融合检测试剂盒(荧光PCR法)检测1089例石蜡包埋组织标本中RET、表皮生长因子受体、间变性淋巴瘤激酶、ROS1、KRAS、BRAF和HER2等基因状态。采用免疫组织化学法检测患者组织标本中PD-L1和错配修复相关蛋白的表达。分析患者RET基因融合与年龄、性别、吸烟史、分期、分化程度、病理学类型以及PD-L1、错配修复蛋白等表达的相关性。结果1089例非小细胞肺癌患者中共发现RET基因融合阳性患者22例(2.02%),男性和女性各11例,中位年龄63.5岁。22例RET基因融合阳性患者有20例腺癌,其中腺泡亚型11例,实体亚型5例,贴壁生长型4例;另有鳞状细胞癌(非角化型)和肉瘤样癌(多形性癌)各1例。临床分期Ⅰ~Ⅱ期6例,Ⅲ~Ⅳ期16例。伴有淋巴结转移16例,远处转移11例。RET基因融合阳性患者中有1例伴HER2突变。RET基因融合阳性肺癌患者中PD-L1的阳性比例分数≥1%的占54.5%(12/22)。未发现RET基因融合阳性非小细胞肺癌患者的错配修复蛋白表达存在缺陷。4例RET基因融合阳性患者(腺泡亚型2例、实体亚型2例)接受了普拉替尼靶向治疗,观察到其中2例患者从靶向治疗中获益。结论RET基因融合阳性患者的组织学亚型倾向于腺泡亚型以及实体亚型。RET基因融合阳性患者往往发生于临床分期较晚的患者,通常伴有淋巴结转移。RET基因融合阳性患者可从RET特异性抑制剂靶向治疗中获益。

Objective To investigate the clinicopathological features,treatment and prognosis of patients with RET fusion positive non-small cell lung cancer(NSCLC).Methods A total of 1089 NSCLCs were retrieved at Affiliated Hospital of Jiangnan University from August 2018 to April 2020.In all cases,multiple gene fusion detection kits(fluorescent PCR method)were used to detect the gene status of RET,EGFR,ALK,ROS1,KRAS,BRAF and HER2;and immunohistochemical method was used to detect the expression of PD-L1 and mismatch repair related proteins.The correlation between RET-fusion and patients′age,gender,smoking history,tumor stage,grade,pathologic type,and PD-L1,mismatch repair related protein expression was analyzed.Results There were 22 cases(2.02%)detected with RET fusion-positive in 1089 NSCLC patients,in which 11 males and 11 females;and the median age was 63.5 years.There were 20 adenocarcinomas,including 11 acinar predominant adenocarcinoma(APA),five solid predominant adenocarcinoma(SPA)and four lepidic predominant adenocarcinoma(LPA);There were one case each of squamous cell carcinoma(non-keratinizing type)and sarcomatoid carcinoma(pleomorphic carcinoma).There were 6 and 16 patients with RET fusion-positive who were in stageⅠ-ⅡandⅢ-Ⅳrespectively,and 16 cases with lymph node metastasis,11 cases with distant metastasis.Among RET fusion-positive cases,one was detected with HER2 co-mutation.The tumor proportion score of PD-L1≥1%in patients with RET fusion positive lung cancer was 54.5%(12/22).Defects in mismatch repair protein expression were not found in patients with RET fusion positive NSCLC.Four patients with RET fusions positive(two cases of APA and two cases of SPA)received pratinib-targeted therapy,and two showed benefits from this targeted therapy.Conclusions The histological subtypes of RET fusions positive NSCLC are more likely to be APA or SPA.RET fusion-positive NSCLC patients are associated with advanced clinical stage,lymph node metastases,and they may benefit from targeted therapy with RET-specific inhibitors.