Preliminary Report: The Relevance of Tumor Necrosis Factor-α in Acquired Primary Lymphedema-A Histopathological Investigation.

Background: Lymphedema includes primary lymphedema (P-LE) and secondary lymphedema (S-LE), which is a chronic progressive disease. The former group is further classified as congenital and acquired P-LE (AP-LE); its etiology is unclear, and only a few studies on its pathophysiology exist. We hypothesized that an autoimmune disease or self-inflammatory mechanism occurs in lymphatic vessels, leading to obstruction. Methods and Results: We enrolled 46 patients with lymphedema who underwent lymphaticovenous anastomosis (LVA) from January to October 2015. Collecting lymph ducts were obtained during LVA. We performed hematoxylin/eosin staining and immunostaining for LYVE-1, IL-1 beta, IL-6, and TNF-alpha. There were no substantial histological differences between the two types of lymphedema, whereas some differences in expression of inflammatory cytokines, including interleukin (IL)-1 beta and tumor necrosis factor (TNF)-alpha, were observed. Only a few inflammatory cells could be seen around the vessels. Although no significant differences in expression of IL-1 beta were found between AP-LE and S-LE, TNF-alpha was more highly expressed in the smooth muscle layer in AP-LE patients than in S-LE patients. There were no significant morphological differences in the collecting ducts of lymphatic vessels between S-LE and P-LE. Nevertheless, higher levels of TNF-alpha accumulation were found in the thick smooth muscle layer of P-LE patients than in that of S-LE patients. Conclusion: TNF-alpha-related inflammation in collecting ducts of lymphatic vessels is an important characteristic of the pathology of P-LE. TNF-alpha inhibitors might improve symptoms of AP-LE.