Pathologic assessment and staging of multiple non-small cell lung carcinomas: A paradigm shift with the emerging role of molecular methods.

Non-small cell lung carcinomas (NSCLC) commonly present as two or more separate tumors. Biologically, this encompasses two distinct processes: separate primary lung carcinomas (SPLCs), representing independently arising tumors, and intrapulmonary metastases (IPMs), representing intrapulmonary spread of a single tumor. The advent of computed tomography imaging has substantially increased the detection of multifocal NSCLC. The strategies and approaches for distinguishing between SPLCs and IPMs have evolved significantly over the years. Recently, genomic sequencing of somatic mutations has been widely adopted to identify targetable alterations in NSCLC. These molecular techniques have enabled the ability to reliably discern clonal relationships among multiple NSCLC in clinical practice. However, a standardized approach to evaluating and staging multiple NSCLC using molecular methods is still lacking. Here, we review the historical context and provide an update on the growing applications of genomic testing as a clinically relevant benchmark for determining clonal relationships in multiple NSCLC, the practice that we have designated “comparative molecular profiling”. We examine the strengths and limitations of morphology-based distinction of SPLCs vs IPMs, and highlight pivotal clinical and pathological insights that have emerged from studying multiple NSCLC using genomic approaches as a gold standard. Lastly, we suggest a practical approach for evaluating multiple NSCLC in the clinical setting, considering the varying availability of molecular techniques.