Adipose Tissue in Lymphedema: A Central Feature of Pathology and Target for Pharmacologic Therapy

Lymphedema is a chronic condition of impaired lymphatic flow that results in limb swelling and debilitation. The pathophysiology of lymphedema is characterized by lymphatic stasis that triggers inflammation, fibrosis, and adipose tissue deposition in the extremities. Most often, this condition occurs in cancer survivors in the years after treatment with combinations of surgery, radiation, or chemotherapy, with the major risk factor being lymph node dissection. Interestingly, obesity and body mass index are independent risk factors for development of lymphedema, suggesting interactions between adipose and lymphatic tissue biology. Currently, treatment of lymphedema involves palliative approaches, including compression garments and physical therapy, and surgical approaches, including liposuction, lymphovenous bypass, and vascularized lymph node transfer. Emerging lymphedema therapies that focus on weight loss or reducing inflammation have been tested in recent clinical trials, yielding mixed results with no effect on limb volumes or changes in bioimpedance measurements. These studies highlight the need for novel therapeutic strategies that target the driving forces of lymphedema. In this light, animal models of lymphedema demonstrate a role of adipose tissue in the progression of lymphedema and suggest these processes may be targeted in the treatment of lymphedema. Herein, we review both conventional and experimental therapies for lymphedema as well as the defining characteristics of its pathophysiology. We place emphasis on the aberrant fibroadipose tissue accumulation in lymphedema and propose a new approach to experimental treatment at the level of adipocyte metabolism.