Fibrosis and secondary lymphedema: chicken or egg?

Raghu P. Kataru, Itay Wiser, Jung Eun Baik, Hyeung Ju Park, Sonia Rehal, Jin Yeon Shin, And Babak J. Mehrara. Translational Research 2019; 209:6876

Click to read the abstract

Fibrosis and secondary lymphedema: chicken or egg?

Raghu P. Kataru, Itay Wiser, Jung Eun Baik, Hyeung Ju Park, Sonia Rehal, Jin Yeon Shin, And Babak J. Mehrara. Translational Research 2019; 209:6876

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.

Main findings

  • Recent studies have paradoxically shown that VEGF-C expression in lymphedematous tissues and in the serum of patients with LE is increased (suggesting that a deficiency of VEGFC is not causal) and that this response may contribute to the pathologic changes of the disease by increasing inflammation and blood vessel leakiness.
  • These findings suggest that lymphatic injury or a deficiency of lymphangiogenic growth factors alone is insufficient to cause the development of LE, and that other pathologic cells and events that either inhibit regeneration of functional lymphatic vessels or soft tissue changes that impair lymphatic transport function (or both) are necessary for the development of the disease.
  • A lymphatic injury is simply an initiating event and that a series of other pathologic changes are required for manifestation of the disease.
  • Fibroadipose tissue deposition and skin fibrosis in LE is progressive, and they have shown that the initial lymphatics become encased by thick collagen bundles in this process. Other clinical studies have shown that collecting lymphatics in late-stage LE become increasingly sclerosed, with the proliferation of smooth muscle cells and obliteration of the lumen.
  • Fibrosis also provides a rationale for the clinical risk factors of LE such as obesity or radiation, since these stimuli independently increase tissue fibrosis.
  • They hypothesize that lymphatic injury initiates downstream changes that promote fibrosis and, once a critical threshold is reached, then LE develops. If this threshold is not reached for whatever reason, then the patient remains asymptomatic. This may be the reason why some patients develop LE years after the initial injury, and a minor inciting event, such as an infection or injury, precedes the development at that time.
  • Most inflammatory cells present in lymphedematous tissues are CD4+. Moreover, we found that the severity of breast cancer-related LE positively correlated with the number of infiltrating CD4+ cells. Thus, patients with more severe LE (eg, stage 3) had a statistically increased number of CD4+ cells, as compared with women with milder forms of the disease (stage 1 or 2). Even minor lymphatic injury, in the form of lymph node dissection in which there is very limited tissue swelling, resulted in accumulation of CD4+ cells.
  • They showed that mice lacking T cells in general or mice with targeted deletion of CD4, in contrast, to control mice, did not develop tissue fibrosis or subsequent LE, suggesting that CD4+ cells play a causal role in the development of the disease.
  • A lymphatic injury is simply an initiating event, setting off a series of downstream changes that in some patients results in the development of LE. These changes include chronic T cell inflammatory reactions, infiltration of a mixed Th1/Th2 cell population, production of proinflammatory and profibrotic cytokines, and progressive fibroadipose tissue deposition. Developing therapies targeting these pathways may provide novel treatment options.