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

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. Key words: Folate receptor; Neoplastic cells, circulating; Pulmonary nodules; Lung neoplasms; Subcentimeter nodules