Malignant Transformation of Musculoskeletal Lesions with Imaging–Pathology Correlation—Part 1: Bone Lesions

Background/Objectives: Malignant transformation of bone lesions, although rare, poses a major diagnostic and clinical challenge. Common benign lesions (e.g., osteochondroma, enchondroma, fibrous dysplasia, giant cell tumor), non-tumorous conditions (e.g., chronic osteomyelitis, irradiated bone, infarction), and low-grade malignancies (e.g., low-grade osteosarcoma, chondrosarcoma) can evolve into aggressive malignancies through distinct genetic, molecular, and microenvironmental pathways. Recognizing early malignant transformation on imaging is crucial for timely diagnosis and management. Methods: This review synthesizes current imaging characteristics, pathologic mechanisms, and clinical risk factors associated with malignant transformation of benign and low-grade malignancy bone lesions. Results: Atypical imaging findings and inaccurate biopsies can delay diagnosis. Aggressive features—such as cortical destruction, heterogeneous enhancement, and loss of internal matrix—should prompt further pathologic evaluation. Advanced imaging and a multidisciplinary approach with integrated clinicoradiologic–pathologic review are essential to minimize missed diagnoses. Patients with risk factors such as genetic syndromes, prior denosumab therapy, inadequate surgery, or prior radiation therapy require close monitoring or timely intervention. Conclusions: Radiologic–pathologic correlation remains central to distinguishing benign from malignant lesions. This review article emphasizes a comprehensive imaging-pathology overview of benign and low-grade malignancy bone lesions with malignant potential, aiming to improve diagnostic accuracy and outcomes in orthopedic oncology.