Comprehensive Pathological Analyses in Lung Squamous Cell Carcinoma Single Cell Invasion, Nuclear Diameter, and Tumor Budding Are Independent Prognostic Factors for Worse Outcomes

Introduction: For lung squamous cell carcinomas, there are no pathological findings that have been universally accepted as prognostic factors, with the exception of pathological stage. Tumor budding and nuclear grade have been recognized as a poor prognostic factor in other carcinomas. In this study, we investigated whether pathological findings could determine prognosis in lung squamous cell carcinomas. Methods: All available tumor slides from patients with surgically resected, solitary lung squamous cell carcinomas (1999-2009) were reviewed (n = 485; stage I/II/III, 281/136/68). Tumors were evaluated for differentiation, subtypes (keratinizing, nonkeratinizing, basaloid pattern, papillary growth, and clear cell feature), tumor nest size (tumor budding and single cell invasion), and nuclear grade (nuclear diameter and mitosis). Overall survival (OS) was estimated using the Kaplan-Meier method (stratified by pathological stage), and group differences were investigated using the stratified log-rank test and the Cox proportional hazards model. Results: OS was significantly decreased in patients with versus without single cell invasion (p = 0.002 for the entire tumor and p = 0.001 for tumor edge), with large versus small nuclei (p = 0.011), and with high versus low grade tumor budding (p < 0.001 for maximum and p = 0.007 for total). In multivariate analyses, single cell invasion (hazard ratio [HR], 1.47-1.49), nuclear diameter (HR, 1.09-1.33), and tumor budding (HR, 1.04) were independent prognostic factors of OS. However, histologic subtyping including keratinizing, nonkeratinizing, basaloid, and clear cell subtypes did not show prognostic significance. Conclusions: Pathological factors can help stratify prognosis in patients with lung squamous cell carcinomas.