Malignant Transformation of Diabetic Foot Ulcer: Pathophysiology, Molecular Mechanisms, and Clinical Implications

Diabetic foot ulcers (DFUs) are a serious complication of diabetes mellitus and are associated with high morbidity, risk of amputation, and increased mortality. Although DFUs typically remain a chronic, non-healing wound, a small portion of DFUs may undergo malignant transformation. The subsequent malignancies are skin cancers such as squamous cell carcinoma (SCC), basal cell carcinoma, or melanoma. Understanding the pathophysiology of DFUs and the molecular and clinical determinants that contribute to their potential malignant transformation if crucial for clinical management. Chronic inflammation, dysregulation of cytokine signaling, faulty immune surveillance, and impaired wound healing all play a role in creating a tumor-permissive environment for the diabetic foot. This review highlights molecular mechanisms driving this transformation, including, vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) pathway dysregulation, hypoxia-inducible factor 1-alpha (HIF-1α) mediated angiogenic signaling, chronic osteomyelitis, and oxidative stress, which can collectively promote progression to malignancies, most notably cutaneous squamous cell carcinoma. Classic examples like Marjolin’s ulcer demonstrate how chronic injury can drive carcinogenesis, reinforcing the importance of vigilant DFU management. Connecting findings across clinical reports and mechanistic studies reveals that understanding DFU carcinogenesis is essential for earlier detection, informed targeted treatment, and improved patient outcomes.