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Review
. 2023 Feb 1;151(2):330e-341e.
doi: 10.1097/PRS.0000000000009866. Epub 2022 Nov 15.

The Vicious Circle of Stasis, Inflammation, and Fibrosis in Lymphedema

Stav Brown  1 , Joseph H Dayan  1 , Raghu P Kataru  1 , Babak J Mehrara  1
Affiliations
Review

The Vicious Circle of Stasis, Inflammation, and Fibrosis in Lymphedema

Stav Brown et al. Plast Reconstr Surg. .

Abstract

Lymphedema is a progressive disease of the lymphatic system arising from impaired lymphatic drainage, accumulation of interstitial fluid, and fibroadipose deposition. Secondary lymphedema resulting from cancer treatment is the most common form of the disease in developed countries, affecting 15% to 40% of patients with breast cancer after lymph node dissection. Despite recent advances in microsurgery, outcomes remain variable and, in some cases, inadequate. Thus, development of novel treatment strategies is an important goal. Research over the past decade suggests that lymphatic injury initiates a chronic inflammatory response that regulates the pathophysiology of lymphedema. T-cell inflammation plays a key role in this response. In this review, the authors highlight the cellular and molecular mechanisms of lymphedema and discuss promising preclinical therapies.

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Figures

Figure 1:
Figure 1:. Indocyanine green (ICG) lymphography showing anatomy of normal and stage I lymphedema arms.
(A) Patent, well-defined, linear collecting lymphatic vessels identified in the volar aspect of a healthy arm. No dermal backflow is observed. (B) Hyperplastic, irregularly shaped lymphatic vessels (red arrows) identified in the volar aspect of a stage I lymphedema arm (yellow arrow points to injection site).
Figure 2:
Figure 2:. Indocyanine green (ICG) lymphography showing anatomy of stage II and III lymphedema arms.
(A) Moderate number of collecting lymphatic vessels can be seen with segmental dermal back flow (green arrows) and hyperplastic lymphatic vessels (red arrows) in the dorsal aspect of a stage II lymphedema arm. (B) Diffuse dermal backflow can be seen throughout the entire arm (green line) in the dorsal aspect of a stage III lymphedema arm. No recognizable patent collecting lymphatic vessels can be seen.
Figure 3:
Figure 3:. The role of dysregulated T cells in lymphedema development.
Th, T-helper cells; IL, interleukin; IFN-γ, interferon gamma; TGF-β1, transforming growth factor β1; Tregs, regulatory T cells; Mφ, macrophage; NPs, neutrophils; DCs, dendritic cells. (Created with Biorender.com.)
Figure 4:
Figure 4:. The role of macrophages in lymphedema development
IL, interleukin; VEGF, vascular endothelial growth factor; iNOS, inducible nitric oxide synthase; Mφ, macrophage. (Created with Biorender.com.)
Figure 5:
Figure 5:. Schematic diagram of the inflammatory cascade and pathological changes following initial lymphatic injury.
Th, T-helper cells; IL, interleukin; TGF-β1, transforming growth factor β1; CD4, cluster of differentiation 4. (Created with Biorender.com)
Figure 6:
Figure 6:. The vicious cycle of obesity and adipose deposition in lymphedema.
(Created with Biorender.com.)
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