Histology and molecular testing

Lung cancer can be broadly classified into non-small cell carcinoma (NSCLC) and small cell carcinoma (SCC), with the former being further subclassified into adenocarcinoma, squamous cell carcinoma, and other less frequent subtypes. Diagnosis of specific lung cancer types are aided by immunohistochemistry markers, including thyroid transcription factor 1 (TTF-1) for adenocarcinoma, p40/p63 for squamous cell carcinoma, and chromogranin, synaptophysin and CD56 for neuroendocrine carcinomas. In lung adenocarcinoma, histologic growth patterns carry prognostic implications, with lepidic predominant tumors being associated with a good prognosis, while micropapillary and solid predominant tumors carrying a worse prognosis. Lepidic pattern is considered non-invasive (in-situ) tumor, and the currently used 8th edition UICC/AJCC staging system for lung cancer bases the T-stage on size of the invasive component of the tumor. For advanced stage NSCLC patients, testing for predictive biomarkers is essential to guide therapy. These include driver mutations/fusions involving the epidermal growth factor receptor (EGFR), ALK, ROS1, BRAF, KRAS, NTRK1-3, RET and MET genes, as well as aberrant protein expression for Programmed Death Ligand 1 (PD-L1). The list of biomarkers continues to grow as newer therapies are discovered or as they become available. With this ever-increasing number of driver mutations/fusions test requirements, next generation sequencing (NGS) with multiple gene panels is rapidly replacing single gene tests. Moving forward, liquid biopsy to detect circulating tumor DNA is assuming a larger role in molecular diagnostics, monitoring therapeutic response and assessment of minimal residual disease.