Longitudinal Analysis of CYFRA 21-1 Levels in Patients with Pulmonary Nodules: Differential Trajectories Between Benign and Malignant Cases and Impact of Tumor Resection

BackgroundCYFRA 21-1, a cytokeratin-19 fragment, is a validated serum biomarker for non-small cell lung cancer (NSCLC). However, most studies rely on single time-point measurements, limiting its specificity in differentiating malignancy from benign pulmonary conditions. Inspired by the clinical utility of serial PSA measurements in prostate cancer, we investigated whether longitudinal trends in CYFRA 21-1 could enhance diagnostic and monitoring capabilities in patients with pulmonary nodules Methods and FindingsWe analyzed 132 patients with pulmonary nodules, including 41 with lung cancer and 91 with benign diagnoses. CYFRA 21-1 levels were measured serially using electrochemiluminescence assays. Longitudinal trends were assessed using linear mixed-effects models to estimate biomarker trajectories. Subgroup analyses examined differences between benign, untreated cancer, and post-treatment cancer groups, as well as within-patient changes in a subset of 16 cancer patients with both pre- and post-surgical measurements. Log-transformed data were used for the analysis. At baseline, CYFRA 21-1 levels were significantly higher in malignant versus benign nodules. Over time, CYFRA trajectories diverged: benign cases showed slight increases, whereas cancer patients exhibited greater biomarker volatility. In treated cancer patients, trend of CYFRA levels on the natural log scale decline from -0.00137 pre-surgery to - 0.00263 to post-surgery, and both cancer groups showed significantly higher absolute slopes than the benign group (p < 0.05). While pre- vs post-treatment slope differences did not reach significance (p = 0.211), the general pattern indicated that CYFRA 21-1 is a dynamic marker responsive to tumor presence and removal. ConclusionsCYFRA 21-1 exhibits substantial within-patient variability over time, with trajectories that reflect disease state and treatment. These findings suggest that longitudinal monitoring of CYFRA 21-1--analogous to PSA velocity in prostate cancer-- may offer improved diagnostic and prognostic insight in the evaluation of pulmonary nodules. Further studies in larger cohorts are warranted to validate these findings and explore clinical implementation of CYFRA trajectory analysis.