Fibrosis and secondary lymphedema: chicken or egg?

Abstract

Secondary lymphedema is a common complication of cancer treatment resulting in progressive fibroadipose tissue deposition, increased risk of infections, and, in rare cases, secondary malignancies. Until recently, the pathophysiology of secondary lymphedema was thought to be related to impaired collateral lymphatic formation after surgical injury. However, more recent studies have shown that chronic inflammation-induced fibrosis plays a key role in the pathophysiology of this disease. In this review, we will discuss the evidence supporting this hypothesis and summarize recent publications demonstrating that lymphatic injury activates chronic immune responses that promote fibrosis and lymphatic leakiness, decrease collecting lymphatic pumping, and impair collateral lymphatic formation. We will review how chronic mixed T-helper cell inflammatory reactions regulate this process and how this response may be used to design novel therapies for lymphedema.

Figure 1:. Lymphedema chronic inflammatory disease results in swollen limbs with fibroadipose tissue deposition.

This patient underwent surgical resection of a cervical cancer with pelvic lymph node dissection. Her course was complicated by a rapidly progressing and severely debilitating lymphedema of the lower extremity.

Figure 2:. Number of patients in the United States who suffer from lymphedema versus other common chronic disorders.

UC, ulcerative colitis; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; MS, multiple sclerosis; ALS, amyotrophic lateral sclerosis.

Figure 3:. Indocyanine green (ICG) lymphangiography of a normal (upper) and lymphedematous (lower) upper extremity.

Note linear lymphatic collectors draining from the hand (bright spots are the injection sites) up towards the axilla in the normal limb. In contrast, note complete absence of lymphatic channels and accumulation of ICG dye in the skin of the lymphedematous limb.

Figure 4:. Lymphedema results in collagen deposition and fibrosis of capillary (upper panel) and collecting (lower panel) lymphatics in a mouse model of tail lymphedema.

Note accumulation of type I collagen fibers encasing capillary lymphatics in the skin (upper left). Also note proliferation of a-sma positive smooth muscle cells and obliteration of the lumen of collecting lymphatics in lymphedematous tissues (lower left).

Figure 5:. Summary diagram denoting immune cell activation in lymphedema.

Panel 1 demonstrates activation of dendritic cells (DCs) in the skin; panel 2 shows migration of activated DCs to regional lymph nodes and activation of naïve T cells with T cell receptor and co-stimulatory molecule interaction. Activated T cells home to the skin in the lymphedematous limb in response to chemokines expressed by keratinocytes and leukocyte adhesion molecules by blood endothelial cells. Reprinted with permission from Garcia Nores GD et al; Nature Communications. 2018;9(1):1970