Pathological changes of adipose tissue in secondary lymphoedema

BACKGROUND: The pathophysiology of lymphoedema is poorly understood. Current treatment options include compression therapy, resection, liposuction and lymphatic microsurgery, but determining the optimal treatment approach for each patient remains challenging. OBJECTIVES: We characterized skin and adipose tissue alterations in the setting of secondary lymphoedema. METHODS: Morphological and histopathological evaluations were conducted for 70 specimens collected from 26 female patients with lower-extremity secondary lymphoedema following surgical intervention for gynaecological cancers. Indocyanine green lymphography was performed for each patient to assess lymphoedema severity. RESULTS: Macroscopic and ultrasound findings revealed that lymphoedema adipose tissue had larger lobules of adipose tissue, with these lobules surrounded by thick collagen fibres and interstitial lymphatic fluid. In lymphoedema specimens, adipocytes displayed hypertrophic changes and more collagen fibre deposits when examined using electron microscopy, whole-mount staining and immunohistochemistry. The number of capillary lymphatic channels was also found to be increased in the dermis of lymphoedema limbs. Crown-like structures (dead adipocytes surrounded by M1 macrophages) were less frequently seen in lymphoedema samples. Flow cytometry revealed that, among the cellular components of adipose tissue, adipose-derived stem/stromal cells and M2 macrophages were decreased in number in lymphoedema adipose tissue compared with normal controls. CONCLUSIONS: These findings suggest that long-term lymphatic volume overload can induce chronic tissue inflammation, progressive fibrosis, impaired homeostasis, altered remodelling of adipose tissue, impaired regenerative capacity and immunological dysfunction. Further elucidation of the pathophysiological mechanisms underlying lymphoedema will lead to more reliable therapeutic strategies.