Preoperative fractional exhaled nitric oxide in differentiating pulmonary nodules and pathological examination of non-small cell lung cancer: a retrospective cohort study.

BACKGROUND: Lung cancer remains the leading cause of cancer-related mortality worldwide, and preoperative differentiation of pulmonary nodules remains challenging. We aimed to investigate the clinical value of preoperative fractional exhaled nitric oxide (FENO) in distinguishing benign pulmonary nodules from malignant pulmonary nodules and characterizing its relationship with pathological features of non-small cell lung cancer (NSCLC).

METHODS: After exclusions from 1,046 consecutive patients, 550 patients were included and classified into malignant (NSCLC) and benign groups based on postoperative pathological examination. Using the Mann-Whitney U test, FENO levels were compared between the two groups. Receiver operating characteristic (ROC) curve analysis was conducted with the optimal cutoff value determined based on the Youden index. Multivariate binary logistic regression analysis was conducted to assess the independent association of FENO with the malignant behavior of NSCLC. In the malignant group, FENO levels were compared across pathological types, tumor-node-metastasis (TNM) stages, and programmed death-ligand 1 (PD-L1) expression groups using the Mann-Whitney U test and the Kruskal-Wallis H test. Subsequently, multivariate linear regression analysis was conducted to explore the independent association between FENO and PD-L1 expression.

RESULTS: Preoperative levels of FENO were significantly higher in the malignant group than in the benign group {median [interquartile range (IQR)]: 23 [18-29] vs. 16 [12-23] ppb, P<0.001}. The clinical/imaging-based model (including age, sex, smoking, and nodule size) achieved an area under the ROC curve (AUC) of 0.597 [95% confidence interval (CI): 0.537-0.657]. After incorporating FENO into the model, the AUC increased significantly to 0.716 (95% CI: 0.657-0.774), indicating that FENO provided incremental diagnostic value, with an optimal cutoff value of 19.5 ppb (sensitivity =70.9%, specificity =66.4%). After adjusting for confounders, FENO remained independently associated with malignancy [odds ratio (OR) =1.094; 95% CI: 1.060-1.128; P<0.001]. In the malignant group, FENO levels were significantly higher in squamous cell carcinoma than in adenocarcinoma (P<0.01). Furthermore, FENO levels differed significantly across PD-L1 expression groups (P<0.001), but not across TNM stages (P=0.52). Multivariate linear regression showed that PD-L1 high-expression group (≥50%) was independently associated with higher FENO levels compared with the negative group (B=0.211; 95% CI: 0.085-0.336; P=0.001), whereas the low-expression group (1-49%) showed no significant association (B=0.030; 95% CI: -0.028 to 0.231; P=0.11) and squamous histological subtype (B=0.290; 95% CI: 0.141-0.440; P<0.001) were independently associated with FENO levels.

CONCLUSIONS: Preoperative levels of FENO demonstrated moderate diagnostic value for malignant nodules. It also exhibited exploratory associations with the squamous histological subtype and PD-L1 expression. Prospective, multicenter validation is needed before clinical adoption.