Current Biomarkers in Non-Small Cell Lung Cancer—The Molecular Pathologist’s Perspective

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Advances in tissue-based biomarkers have significantly enhanced diagnostic and therapeutic approaches in NSCLC, enabling precision medicine strategies. This review provides a comprehensive analysis of the molecular pathologist’s practical approach to assessing NSCLC biomarkers across various specimen types (liquid biopsy, broncho–alveolar lavage, transbronchial biopsy/endobronchial ultrasound-guided biopsy, and surgical specimen), including challenges such as biological heterogeneity and preanalytical variability. We discuss the role of programmed death ligand 1 (PD-L1) immunohistochemistry in predicting immunotherapy response, the practice of histopathological tumor regression grading after neoadjuvant chemoimmunotherapy, and the application of DNA- and RNA-based techniques for detecting actionable molecular alterations. Finally, we emphasize the critical need for quality management to ensure the reliability and reproducibility of biomarker testing in NSCLC.