Diagnostic accuracy of folate receptor-positive circulating tumor cells in differentiating between benign and malignant pulmonary nodules.

Abstract

Background: Currently, traditional blood biomarkers such as neuron-specific enolase (NSE), carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCCA) etc. are mostly elevated in the late stage of tumour, and patients have already lost the chance of tumour eradication when the relevant indexes are found to be elevated. Therefore, there is a need for blood biomarkers with higher sensitivity, better specificity, and better accessibility. Folate receptor-positive circulating tumor cells (FR⁺CTCs) may have diagnostic value in lung cancer. Nevertheless, there is a scarcity of research exploring the efficacy of FR⁺CTCs in screening pulmonary nodules for lung cancer. The aims of this study were to differentiate between lung cancer and benign pulmonary nodules using FR⁺CTCs in conjunction with blood markers and to develop a composite diagnostic model for pulmonary nodules.

Methods: Based on the inclusion and exclusion guidelines, we retrospectively analysed 1,135 patients with pulmonary nodules who underwent tissue biopsy or surgical resection after FR⁺CTC testing, assessed the histopathological findings by a specialised pathologist, and collected and compared demographic characteristics, blood markers, imaging and pathological parameters in malignant and benign patients. The random forest model was used to screen for indicators and to establish a composite index of blood biomarkers. The performance of single factors or the integrated model were estimated by applying receiver operating characteristic (ROC) analysis.

Results: A total of 612 patients were included in the lung cancer group, predominantly presenting with stage I adenocarcinomas (n=458). The median age was 54 years, and 43.1% of the patients were male. In comparison, 523 patients were included in the benign pulmonary nodules group, with a median age of 53 years and 46.8% male. No significant differences were identified between the two groups with regard to gender or age (P>0.05). The level of FR⁺CTCs in the lung cancer group was significantly higher than that in the benign nodule group (P<0.001). The white blood cell (WBC) and cytokeratin 19 fragment antigen 21-1 (CYFRA21-1) levels were significantly higher in the lung cancer group than in the benign nodule group (P<0.001 and P=0.01, respectively). FR⁺CTC level was associated with the pathological subtype (P=0.02), WBC (P<0.001), and lactate dehydrogenase (LDH) level (P=0.01). In both groups, the FR⁺CTC level was higher in the single-nodule group than in the multiple-nodule group (P=0.002 and P=0.040, respectively). The diagnostic sensitivity and specificity of FR⁺CTCs for lung cancer at a cutoff of 8.7 FU/3 mL was 61.9% and 75.0%, respectively. Increasing the cutoff to 1.5 times (13.1 FU/3 mL) and 2 times (17.4 FU/3 mL) improved the specificity to 90.8% and 95.6%, respectively. The combination of FR⁺CTCs with WBC, procalcitonin, and LDH resulted in an area under the curve of 0.976 [95% confidence interval (CI): 0.910-1.000], a sensitivity of 100.0%, and a specificity of 85.7%.

Conclusions: FR⁺CTC was proven to be a viable blood biomarker for aiding in the early detection of lung cancer. The combined model based on FR⁺CTC showed substantially greater accuracy than did any single biomarker in patients with pulmonary nodules.