Biomarkers for the diagnosis of indeterminate pulmonary nodules: are we there yet?

Indeterminate pulmonary nodules (IPNs), which are nodules that cannot be classified as definitively benign or malignant at the time of detection, are now diagnosed on the order of millions per year. Management of IPNs remains heavily debated, and routine practice ultimately involves some balance of overall clinical risk assessment and additional diagnostic tests or procedures which may generate significant risk, cost, and worry. Biomarkers are biologically based tests or indicators capable of accurately characterizing the physiologic properties of homeostasis and disease that are not otherwise easily evaluated by the clinician. Accurate biomarkers thereby serve as reliable surrogates for biological aberrancy, and importantly for the field of diagnostics, can signal early pathology before it becomes clinically detectable. In the realm of IPNs, biomarker development seeks to address a growing need for noninvasive adjunct tools that can be leveraged clinically to add clarity where diagnostic uncertainty exists. Here, effective diagnostic biomarkers have the potential to hone clinical management, accelerate treatment when indicated, and curb added unnecessary diagnostics. In this review article, the authors highlight the role for biomarkers in the diagnosis of IPNs, outline the methodology for successful biomarker development, and discuss contemporary IPN biomarker research and the remaining challenges and future directions for the field.