Histopathologic Features of Lymphedema: A Molecular Review

Abstract

An estimated 5 million people in the United States are affected by secondary lymphedema, with most cases attributed to malignancies or malignancy-related treatments. The pathogenesis of secondary lymphedema has historically been attributed to lymphatic injury or dysfunction; however, recent studies illustrate the complexity of lymphedema as a disease process in which many of its clinical features such as inflammation, fibrosis, adipogenesis, and recurrent infections contribute to on-going lymphatic dysfunction in a vicious cycle. Investigations into the molecular underpinning of these features further our understanding of the pathophysiology of this disease and suggests new therapeutics.

Keywords: adipogenesis; fibrosis; immunity; inflammation; inflammatory skin conditions; lymphedema; recurrent infections.

Figure 1

Representative immunohistochemistry images demonstrating CD4+ (upper), IL-4+ (middle), and IL-13+ (lower) cells in matched human biopsy specimens comparing lymphedematous and contralateral normal upper extremities. Reprinted with permission from supplemental figure 1 [26].

Figure 2

Schematic showing proposed pathophysiologic consequences following initial lymphatic injury. The accumulation of lymphatic fluid incites adipogenesis and an inflammatory response that sets off a cascade of molecular events leading to lymphatic impairment. Notably, of the inflammatory response, CD4+ T cell activation has been shown to be both necessary and sufifficent for the development of lymphedema. CD4+ T cell activation induces elaboration of T helper 2 (Th2) cytokines IL-4 and IL-13, along with transforming growth factor-β1 (TGF-β1), that contribute to lymphatic dysfunction either directly or indirectly by promoting tissue fibrosis, decreasing lymphatic pumping, impairing collateral lymphatic formation, and increasing lymphatic leakiness. The culminative effect is worsening of lymphatic fluid stasis.