Plastic Surgery Research Council
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Presenter: Daniel Cuzzone, MD
Co-Authors: Zampell JC; Weitman E; Aschen S; Farias-Eisner G; Ghanta S; Albano N; Mehrara BJ
Memorial Sloan Kettering Cancer Center

Background: Lymphedema is a common complication of cancer treatment; however, current diagnostic options are limited and rely primarily on limb circumference or volume measurements. Identification of a serum marker for lymphedema may facilitate diagnosis and response to treatment. Lymphedema is characterized clinically by adipose tissue deposition and inflammation; therefore, we investigated serum and tissue levels of interleukin-6 (IL-6), an important physiologic regulator of these processes.

Methods: We used a variety of mouse models to test the hypothesis that lymphatic fluid stasis increases the expression of IL-6, including microsurgical disruption of the superficial and deep lymphatics of the tail and axillary lymph node dissection (ALND). In order to translate our findings clinically, we analyzed IL-6 expression in serum samples obtained from breast cancer survivors with or without lymphedema. Finally, we analyzed tissue expression of IL-6 in matched biopsy samples obtained from lymphedematous and contralateral normal limbs of patients with lymphedema.

Results: We found a significant elevation of IL-6 levels locally in regions of lymphatic fluid stasis in both the mouse tail model (p<0.001) as well as the mouse ALND model (p=0.009). Similarly, serum levels of IL-6 were elevated in mice with tail lymphedema and after ALND as compared to sham surgical controls. These findings correlated with a statistically significant increase in local tissue expression of IL-6 expression (p<0.001) and activation of its downstream mediator STAT-3 in lymphedematous clinical samples as compared to contralateral normal tissue biopsies. In addition, we noted significant increases in serum levels of IL-6 (p=0.004) in patients with lymphedema as compared with patients without lymphedema.

Conclusions: Lymphatic fluid stasis potently upregulates the expression of IL-6 both locally and systemically in mouse models of lymphedema as well as in patients with lymphedema. These findings suggest that serum levels of IL-6 may be a useful means of diagnosing lymphedema as well as assessing response to treatment.

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