Malignant Transformation and Progression of Musculoskeletal Lesions with Imaging–Pathology Correlation—Part 2: Soft Tissue Lesions

Background/Objectives: Malignant transformation of soft tissue lesions is uncommon but represents a significant diagnostic challenge with substantial clinical consequences. This spectrum encompasses four interrelated processes but biologically distinct processes: (1) true malignant transformation of benign lesions; (2) dedifferentiation of low-grade or intermediate malignancies; (3) secondary malignancy arising in chronic inflammatory or non-neoplastic conditions; and (4) apparent progression related to tumor heterogeneity and sampling error. Although these four entities involve biologically distinct mechanisms, they are grouped under “malignant progression” for conceptual clarity. While this umbrella approach has limitations due to biological heterogeneity, this unified radiologic framework aims to supplement, rather than oversimplify, their distinct biological behaviors. Representative examples include neurofibroma and epidermal inclusion cyst among benign lesions; atypical lipomatous tumor/well-differentiated liposarcoma, dermatofibrosarcoma protuberans, and solitary fibrous tumor among lesions showing dedifferentiation or malignant progression; and chronic inflammatory or scar-related conditions and previously irradiated tissue associated with secondary malignancy. Some lesions that appear to progress during follow-up may represent initial underdiagnosis rather than true biologic progression. Methods: This narrative review summarizes current imaging features, underlying pathologic mechanisms, and clinical risk factors associated with these processes in soft tissue lesions. Particular emphasis is placed on radiologic–pathologic correlation and conditions prone to histopathologic misinterpretation. Results: Imaging red flags—including interval or rapid growth, deep fascial invasion, heterogeneous enhancement, perilesional edema, and necrosis—should raise concern for malignant progression across these categories. However, overlapping imaging features and sampling errors may result in pathologic misdiagnosis and delayed treatment. Particularly, atypical lipomatous tumors are frequently misdiagnosed as simple lipomas, while fibrosarcomas may be erroneously interpreted as aggressive fibromatosis. Advanced imaging and multidisciplinary review may help reduce diagnostic errors. Patients with predisposing factors such as genetic syndromes, chronic inflammation, prior burns, or previous radiation exposure warrant close surveillance. Conclusions: Accurate diagnosis of soft tissue lesions with true malignant transformation, dedifferentiation, or secondary malignancy—as well as recognition of diagnostic pitfalls—is essential for appropriate management. Integrated radiologic–pathologic assessment may help improve diagnostic accuracy and clinical decision-making in soft tissue oncology.