Rationale and ObjectivesThe preoperative diagnosis of small prevascular mediastinal nodules (SPMNs) presents a challenge, often leading to unnecessary surgical interventions. Our objective was to develop a nomogram based on preoperative CT radiomics features, serving as a non-invasive diagnostic tool for SPMNs. Materials and MethodsPatients with surgically resected SPMNs from two medical centers between January 2018 and December 2022 were retrospectively reviewed. Radiomics features were extracted and screened from preoperative CT images. Logistic regression was employed to establish clinical, radiomics, and hybrid models for differentiating thymic epithelial tumors (TETs) from cysts. The performance of these models was validated in both internal and external test sets by area under the receiver operating characteristic curve (AUC), while also comparing their diagnostic capability with human experts. ResultsThe study enrolled a total of 363 patients (median age, 53 years [IQR:45-59 years]; 175 [48.2%] males) for model development and validation, including 136 TETs and 227 cysts. Lesions' enhancement status, shape, calcification, and rad-score were identified as independent factors for distinction. The hybrid model demonstrated superior diagnostic performance compared to other models and human experts, with an AUC of 0.95 (95% CI:0.92-0.98), 0.94 (95% CI:0.89-0.99), and 0.93 (95% CI:0.83-1.00) in the training set, internal test set, and external test set respectively. The calibration curve of the model demonstrated excellent fit, while decision curve analysis underscored its clinical value. ConclusionThe radiomics-based nomogram effectively discriminates between the most prevalent types of SPMNs, namely TETs and cysts, thus presenting a promising tool for treatment guidance.