Abstract
Head and neck lymphedema (HNL) is a disfiguring disease affecting over 90% of patients treated for head and neck cancer. Animal models of lymphedema are used to test pharmacologic and microsurgical therapies; however, no animal model for HNL is described in the literature to date. In this study we describe the first reproducible rat model for HNL. Animals were subjected to two surgical protocols: (1) lymphadenectomy plus irradiation; and (2) sham surgery and no irradiation. Head and neck expansion was measured on post-operative days 15, 30 and 60. Magnetic resonance imaging (MRI) was acquired at the same time points. Lymphatic drainage was measured at day 60 via indocyanine green (ICG) lymphography, after which animals were sacrificed for histological analysis. Postsurgical lymphedema was observed 100% of the time. Compared to sham-operated animals, lymphadenectomy animals experienced significantly more head and neck swelling at all timepoints (P < 0.01). Lymphadenectomy animals had significantly slower lymphatic drainage for 6 days post-ICG injection (P < 0.05). Histological analysis of lymphadenectomy animals revealed 83% greater subcutis thickness (P = 0.008), 22% greater collagen deposition (P = 0.001), 110% greater TGFβ1+ cell density (P = 0.04), 1.7-fold increase in TGFβ1 mRNA expression (P = 0.03), and 114% greater T-cell infiltration (P = 0.005) compared to sham-operated animals. In conclusion, animals subjected to complete lymph node dissection and irradiation developed changes consistent with human clinical postsurgical HNL. This was evidenced by significant increase in all head and neck measurements, slower lymphatic drainage, subcutaneous tissue expansion, increased fibrosis, and increased inflammation compared to sham-operated animals.
Highlights
Lymphedema is a debilitating condition caused by insufficiency of the lymphatic system that affects over 250 million individuals worldwide[1]
Secondary head and neck lymphedema (HNL) is frequently seen in patients treated for head and neck cancer, which affects over 550,000 people annually
Since lymphedema in its early stages is known to result in adipose tissue hypertrophy, image analysis of Magnetic resonance imaging (MRI) scans was performed to quantify the volume of fat present within the head and neck region of lymphadenectomy and sham rats
Summary
Lymphedema is a debilitating condition caused by insufficiency of the lymphatic system that affects over 250 million individuals worldwide[1] It is characterized by progressive soft tissue swelling and can carry a significant disease burden[2]. Secondary head and neck lymphedema (HNL) is frequently seen in patients treated for head and neck cancer, which affects over 550,000 people annually. Given the challenges of performing compression bandaging and manual lymphatic drainage on structures in the head and neck, standard treatment for other forms of lymphedema cannot be reasonably and reproducibly used to manage HNL. Our primary objective was to develop the first reproducible animal model for HNL that can be used by future researchers to test therapies specific to this underdiagnosed and poorly managed disease
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