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Effect Of Unilateral Lymphadenectomy In A Pre-clinical Animal Model Of Secondary Head And Neck Lymphedema
Andrea Y. Lo, BS, Giulia Daneshgaran, BS, Melissa Bircan, Seung Ju Bae, MD, Roy P. Yu, BS, Sarah X. Wang, Haig Manoukian, Wan Jiao, MD, PhD, Alex K. Wong, MD.
Keck School of Medicine of USC, Los Angeles, CA, USA.

PURPOSE: Head and neck lymphedema (HNL) is a disfiguring disease that affects over 75% of patients treated for head and neck cancer (HNC). Animal models of lymphedema are used to test pharmacologic and microsurgical therapies, which can offer improved outcomes compared to standard conservative therapies. However, no animal model for HNL has been described in peer-reviewed literature. We have recently described a robust rat HNL model based on complete bilateral deep and superficial lymphadenectomy using our Prox-1 eGFP transgenic rats which facilitate real time in situ lymph node localization. A limitation of this model is that most patients with HNC have tumors which only require unilateral lymph node dissection. Our aim was to determine if unilateral lymphadenectomy is sufficient to produce clinically relevant HNL and to compare this phenotype to that of animals that receive bilateral lymphadenectomy.
METHODS:
Rats were subjected to two surgical protocols: (1) unilateral lymphadenectomy with post-operative irradiation (n=8) and (2) sham surgery with no irradiation (n=9). In the lymphadenectomy group, the superficial and deep cervical lymph nodes were dissected unilaterally. For both groups, neck hemi-circumference and cheek-to-midline distance was quantified on the operated side and reported as "percent change from unoperated side" in order to assess head and neck expansion on post-operative days 15, 30, 45, and 60. Finally, lymphatic clearance was measured on post-operative day 60 by injected indocyanine green (ICG) lymphography.
RESULTS: Neck hemi-circumference on the operated side was significantly greater in the lymphadenectomy group than in the sham surgery group at all post-operative time points (p<0.01). Cheek-to-midline distance on the operated side was also significantly greater in lymphadenectomy animals on post-operative days 30, 45, and 60 (p<0.001, p<0.05, p<0.01). Lymphographic analysis revealed that lymphatic clearance was considerably slower 12 hours after ICG injection in the lymphadenectomy group, indicating reduced drainage secondary to lymphatic injury (p<0.01) .
Neck hemi-circumference on the operated side was significantly greater in the lymphadenectomy group than in the sham surgery group at all post-operative time points (p<0.01). Cheek-to-midline distance on the operated side was also significantly greater in lymphadenectomy animals on post-operative days 30, 45, and 60 (p<0.001, p<0.05, p<0.01). Lymphographic analysis revealed that lymphatic clearance was considerably slower 12 hours after ICG injection in the lymphadenectomy group, indicating reduced drainage secondary to lymphatic injury (p<0.01) . CONCLUSION: Unilateral cervical lymph node resection in rats leads to significant head and neck expansion and reduced lymphatic clearance, both of which are consistent with the development of HNL. The phenotype is sustained for at least 60 days with minimal reversion to normal lymphatic function. Our unilateral cervical lymphatic injury animal model is clinically relevant and can be used to better understand HNL and test microsurgical procedures that can ameliorate HNL.


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