Narrative review: indeterminate pulmonary nodules

The detection of indeterminate pulmonary nodules (IPNs) has become common through more frequent use of sensitive axial imaging and implementation of lung cancer screening protocols. Differentiating benign and malignant lesions can be challenging, particularly when nodules are small, but presents a critical opportunity to detect early cancers and improve patient outcomes. There are many noninvasive and invasive approaches to characterizing IPNs, representing an ongoing clinical need and an area of active research. This article will first provide a brief overview of the epidemiology of IPNs and discuss the implications of lung cancer screening. It will then review the use of clinical scores, radiographic features, and noninvasive molecular approaches in risk stratifying IPNs with an emphasis on sub-centimeter lesions. In particular, the evidence underlying peripherally accessible DNA, RNA, and protein-based "liquid biopsies" will be explored. This article will then describe techniques to optimize the diagnostic yield of minimally invasive tissue sampling methods including percutaneous transthoracic needle biopsies and endobronchial ultrasound-guided fine needle aspiration, as well as approaches to optimize lesion localization for surgical diagnosis. The review will conclude with a discussion of several molecular tests that provide insight into possible ways to overcome histologically indeterminate or nondiagnostic biopsy results in the future.