Diagnostic and Predictive Immunohistochemistry for Non–Small Cell Lung Carcinomas

Non-small cell lung carcinoma (NSCLC) accounts for significant morbidity and mortality worldwide, with most patients diagnosed at advanced stages and managed increasingly with targeted therapies and immunotherapy. In this review, we discuss diagnostic and predictive immunohistochemical markers in NSCLC, one of the most common tumors encountered in surgical pathology. We highlight 2 emerging diagnostic markers: nuclear protein in testis (NUT) for NUT carcinoma; SMARCA4 for SMARCA4-deficient thoracic tumors. Given their highly aggressive behavior, proper recognition facilitates optimal management. For patients with advanced NSCLCs, we discuss the utility and limitations of immunohistochemistry (IHC) for the "must-test" predictive biomarkers: anaplastic lymphoma kinase, ROS1, programmed cell death protein 1, and epidermal growth factor receptor. IHC using mutant-specific BRAF V600E, RET, pan-TRK, and LKB1 antibodies can be orthogonal tools for screening or confirmation of molecular events. ERBB2 and MET alterations include both activating mutations and gene amplifications, detection of which relies on molecular methods with a minimal role for IHC in NSCLC. IHC sits at the intersection of an integrated surgical pathology and molecular diagnostic practice, serves as a powerful functional surrogate for molecular testing, and is an indispensable tool of precision medicine in the care of lung cancer patients.