Is Lymphedema a Systemic Disease? A Paired Molecular and Histological Analysis of the Affected and Unaffected Tissue in Lymphedema Patients

Abstract

Secondary lymphedema is a chronic, debilitating disease and one of the most common side effects of oncologic surgery, substantially decreasing quality of life. Despite the progress conducted in lymphedema research, the underlying pathomechanisms remain elusive. Lymphedema is considered to be a disease affecting an isolated extremity, yet imaging studies suggest systemic changes of the lymphatic system in the affected patients. To evaluate potential systemic manifestations in lymphedema, we collected matched fat and skin tissue from the edematous and non-edematous side of the same 10 lymphedema patients as well as anatomically matched probes from control patients to evaluate whether known lymphedema manifestations are present systemically and in comparison to health controls. The lymphedematous tissue displayed various known hallmarks of lymphedema compared to the healthy controls, such as increased epidermis thickness, collagen deposition in the periadipocyte space and the distinct infiltration of CD4+ cells. Furthermore, morphological changes in the lymphatic vasculature between the affected and unaffected limb in the same lymphedema patient were visible. Surprisingly, an increased collagen deposition as well as CD4 expression were also detectable in the non-lymphedematous tissue of lymphedema patients, suggesting that lymphedema may trigger systemic changes beyond the affected extremity.