Differentiating multiple primary lung carcinomas (MPLCs) from intrapulmonary metastases (IPMs) remains a critical challenge in the management of patients with multiple non-small cell lung carcinomas (NSCLCs). Although the clinical presentation of MPLCs and IPMs often appears similar, they represent biologically distinct evolutionary processes. In the genomics era, molecular pathology has provided new tools to address this diagnostic challenge in clinical practice. Simultaneously, a multitude of genome research studies have elucidated the evolutionary dynamics underlying tumor initiation, progression, and metastatic divergence which provide a mechanistic framework and underpinning for unambiguous clonality diagnostics. In this review, we aim to bridge the gap between tumor evolution and the dilemma of clonality diagnostics in NSCLC. We first revisit historical approaches to clonality diagnostics from today's genomic perspective. We then systematically discuss how evolutionary principles of oncogenesis are reflected across established and emerging diagnostic approaches, including histomorphology, somatic mutation profiling, fusion detection, copy number aberration analysis, transcriptomics, and methylation testing. Finally, we discuss the limitations and potential opportunities of these approaches in current and future clinical practice. We show that the conceptual integration of tumor evolution into clonality diagnostics is essential for accurate staging and treatment selection to ultimately improve outcomes for patients with multiple lung carcinomas.
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