叶酸受体阳性循环肿瘤细胞检测对肺部亚厘米结节的诊断价值

Diagnostic value of folate receptor-positive circulating tumor cell detection in subcentimeter pulmonary nodules

目的探讨叶酸受体(FR)阳性循环肿瘤细胞(CTC)检测在肺部亚厘米结节(结节最大径≤10mm)良恶性诊断中的价值。方法选择2018年7月至12月首都医科大学宣武医院收治的胸部CT检查显示有最大径≤10 mm的肺小结节患者37例,包括术后病理诊断为早期肺腺癌22例、肺良性病变15例。患者术前均留取静脉血,应用新型配体靶向聚合酶链反应(LT-PCR)检测FR+CTC水平(以自定义的FU/3 ml为单位),应用酶联免疫吸附试验检测癌胚抗原(CEA)、神经元特异性烯醇化酶(NSE)、细胞角蛋白19片段CYFRA21-1、糖类抗原125(CA125)、CA199、胃泌素释放肽前体(pro-GRP)等肿瘤标志物水平。计量资料两组间比较采用t检验,以检测试剂盒说明书指定的CTC值8.70 FU/3 ml为临界值,应用二元logistic回归法分析肺结节为恶性的危险因素;采用kappa一致性检验分析以FR+CTC水平诊断与手术切除标本的病理结果诊断的一致性;绘制受试者工作特征曲线(ROC),评估各指标对肺部亚厘米结节良恶性的诊断效能。结果早期肺腺癌患者FR+CTC表达水平高于肺良性病变患者,差异有统计学意义[(11.0±3.0)FU/3 ml比(7.0±3.7)FU/3 ml,t=-3.327,P=0.001];FR+CTC水平与患者的年龄、性别、吸烟史均无相关性(均P>0.05)。经logistic回归分析显示,FR+CTC水平高为肺结节恶性的危险因素(OR=37.333,95%CI 3.994~349.010,P=0.002)。kappa一致性检验结果显示FR+CTC诊断肺亚厘米结节性质具有一定的准确性(κ=0.627,P<0.01)。ROC分析显示,FR+CTC作为诊断肺结节恶性的指标时,其诊断价值优于CEA、NSE、CYFRA21-1三者联合;FR+CTC的曲线下面积(AUC)为0.830(95%CI 0.639~0.968),诊断灵敏度为72.7%(95%CI 49.6%~88.4%),特异度为93.3%(95%CI 66.0%~99.7%);将FR+CTC、CEA、NSE、CYFRA21-1四者联合诊断肺癌时,AUC为0.776(95%CI 0.614~0.938),诊断灵敏度为86.4%,特异度为73.3%。结论FR+CTC检测对肺部亚厘米结节的良恶性诊断具有较高的价值。

Objective To investigate the value of the folate receptor(FR)-positive circulating tumor cell(CTC)detection in the diagnosis of benign and malignant subcentimeter pulmonary nodules(the maximum diameter≤10 mm).Methods Thirty-seven patients with subcentimeter pulmonary nodules(the chest CT showed the maximum diameter was≤10 mm)in the Xuanwu Hospital of Capital Medical University from July to December 2018 were collected.Among them,22 cases were diagnosed with early stage lung adenocarcinoma by postoperative pathological diagnosis and another 15 cases were benign lung lesion.Venous blood samples from these patients were collected before surgery and then utilized to detect FR+CTC level(defined unit as FU/3 ml)by novel ligand-targeted polymerase chain reaction(LT-PCR),and the enzyme-linked immunosorbent assay was used to detect the levels of tumor markers,including carcinoembryonic antigen(CEA),neuron-specific enolase(NSE),cytokeratin 19 fragment CYFRA21-1,carbohydrate antigen 125(CA125),CA199,pro-gastrin releasing peptide(pro-GRP),etc.The t-test was used to compare the measurement values between the groups.The CTC value 8.70 FU/3 ml described in the detection kit instruction was used as the threshold.The binary logistic regression was used to analyze the risk factors of malignant pulmonary nodules.The kappa consistency test was used to identify the consistency of the diagnosis results obtained by the FR+CTC level and the pathological results of surgically resected specimens.The receiver operating characteristic curve(ROC)was drawn to evaluate the efficiency of each index for the diagnosis of benign and malignant subcentimeter pulmonary nodules.Results The level of FR+CTC in patients with early stage lung cancer was higher than that in patients with benign lung lesion,and the difference was statistically significant[(11.0±3.0)FU/3 ml vs.(7.0±3.7)FU/3 ml,t=-3.327,P=0.001].The level of FR+CTC was not related to the age,gender and smoking history of patients(all P>0.05).Logistic regression analysis indicated that high-level FR+CTC was one of the risk factors for malignant pulmonary nodules(OR=37.333,95%CI 3.994-349.010,P=0.002).The kappa consistency test indicated that the level of FR+CTC used for the diagnosis of lung subcentimeter nodules presented a certain accuracy(κ=0.627,P<0.01).ROC illustrated that the FR+CTC was better than CEA,NSE and CYFRA21-1 when it was used as an indicator for the diagnosis of malignant pulmonary nodules.The area under the curve(AUC)of FR+CTC was 0.830(95%CI 0.639-0.968),and the diagnostic sensitivity and specificity were 72.7%(95%CI 49.6%-88.4%)and 93.3%(95%CI 66.0%-99.7%),respectively.When FR+CTC,CEA,NSE and CYFRA21-1 were combined for lung cancer diagnosis,the AUC,sensitivity and specificity were 0.776(95%CI 0.614-0.938),86.4%and 73.3%,respectively.Conclusion The detection of FR+CTC has a high value in the diagnosis of benign and malignant subcentimeter pulmonary nodules.