Prevascular mediastinal lesions encompass a broad spectrum of entities, ranging from benign cysts to malignant tumors such as thymic epithelial tumors (TETs), lymphoma, and germ cell tumors (GCTs). With the increasing use of computed tomography (CT), incidentally detected, asymptomatic prevascular mediastinal nodules are encountered more frequently in daily practice. However, accurate characterization based on CT alone remains challenging because cystic lesions may exhibit soft-tissue attenuation or pseudoenhancement, resulting in substantial overlap with solid tumors and potential overtreatment. This review mainly focuses on the differential diagnosis of incidentally detected prevascular mediastinal nodules and summarizes their epidemiologic, clinical, and imaging characteristics. Particular emphasis is placed on a practical diagnostic strategy that integrates contrast-enhanced CT for lesion localization and morphologic assessment with magnetic resonance imaging (MRI) for problem-solving. Although lymphomas and GCTs usually present as large symptomatic masses rather than incidental nodules, they are also discussed because they remain important considerations in the differential diagnosis of prevascular mediastinal lesions. MRI provides superior tissue characterization, enabling reliable differentiation of cystic and solid lesions, evaluation of intratumoral architecture, assessment of tumor cellularity using diffusion-weighted imaging and apparent diffusion coefficient values, and more accurate evaluation of local invasion. The selective role of fluorine-18 fluorodeoxyglucose positron emission tomography/CT (FDG-PET/CT), particularly for lymphoma, aggressive malignancies, and disease staging, is also discussed. By integrating imaging findings with epidemiologic information, clinical presentation, and laboratory data, a stepwise diagnostic approach can improve diagnostic confidence, reduce unnecessary invasive procedures, and facilitate appropriate management of prevascular mediastinal nodules.
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