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Background: Although it is well recognized that lymphedema is a common complication of cancer treatment, the true incidence of this disorder is debated. The variability in the reported rates of lymphedema is likely related to the clinical methods used to diagnose it relying in most cases on limb circumference measurements or limb volumes. Therefore, identification of a simple serum marker for lymphedema may facilitate a more accurate and expeditious diagnosis and ultimately lead to improved treatment. Based on the fact that the defining feature of lymphedema is fat deposition, we hypothesized that expression of measurable fat differentiation markers will be increased locally in lymphedematous tissues as well as systemically in the peripheral blood.

Methods: We used a variety of mouse models, including microsurgical disruption of the superficial and deep lymphatics of the tail and axillary lymph node dissection (ALND), to test the hypothesis that lymphatic stasis increases the expression of fat differentiation markers. To translate our findings clinically, we analyzed IL-6 expression in the serum and tissues of breast cancer survivors with or without lymphedema.

Results: Lymphatic stasis in the tail or after ALND significantly increased subcutaneous fat deposition and upregulated adipogenic differentiation genes such as IL-6, CCAAT/enhancer-binding protein alpha (CEPB-a), peroxisome proliferator-activated receptor gamma (PPAR-g), and adiponectin in tissues. Expression of these markers was increased both temporally and spatially in response to gradients of lymphatic stasis. More importantly, mean serum IL-6 levels were increased within 2 weeks of surgery (20-fold increase relative to control, p<0.01) and remained elevated even 6-weeks postop. Similarly, IL-6 expression (number of IL-6⁺ cells) was significantly increased in clinical lymphedematous tissues as compared with normal skin specimens. These findings correlated with a statistically significant increase in serum IL-6 concentrations in patients with lymphedema as compared with breast cancer survivors who did not have lymphedema (p<0.001).

Conclusions: Our results demonstrate that lymphatic stasis potently regulates adipose deposition in tissues by increasing the expression of fat differentiation genes. More importantly, we have shown for the first time that lymphatic stasis increases the expression of IL-6, a critical adipose tissue regulator not only locally but also systemically. These changes can be accurately measured and maybe useful in developing sensitive tests to diagnose and treat lymphedema. In addition, accurate diagnostic tests may be useful in tracking treatment effects of interventions such as microsurgical lymph node transfer, lymphatic bypass, or manual lymphatic massage thereby enabling standardization of efficacy reporting.