Heterogeneous characteristics of lymphatic microvasculatures associated with pulmonary sarcoid granulomas

Pulmonary sarcoidosis is a disorder characterized by noncaseating epithelioid granulomas that are anatomically distributed along lymphogenous routes. Currently, limited information is available about lymphangiogenesis in pulmonary sarcoidosis. To clarify the characteristics of lymphangiogenesis in pulmonary sarcoidosis. The concentrations of vascular endothelial growth factor (VEGF), VEGF-C, and VEGF-D in serum and bronchoalveolar lavage fluid from 65 patients with pulmonary sarcoidosis, 10 with idiopathic pulmonary fibrosis, and 29 healthy volunteers were measured by ELISA. Paraffin-embedded lung tissues obtained from 19 patients were used for immunohistochemical analyses, using primary antibodies against VEGF, VEGF-C, VEGF-D, podoplanin, VEGF receptor (VEGFR)-2, VEGFR-3, and CD73. The serum and bronchoalveolar lavage fluid concentrations of VEGF and VEGF-C were significantly increased in patients with pulmonary sarcoidosis. Immunohistochemical analysis showed that VEGF and VEGF-C were expressed in sarcoid granulomas. Immunostaining with anti-podoplanin antibody for the detection of lymphatic vasculatures showed the presence of usual lymphatics and atypical tubular structures around sarcoid granulomas. Atypical tubular structures were characterized by a thin membrane, with weak expression of podoplanin and a membrane deficit in a part of the borderline. The structures were observed in around 58.6% of the total of 193 granulomas, whereas usual lymphatics were limited in 15.6%. Atypical tubular structures were coexpressed with VEGFR-2, but not VEGFR-3, whereas VEGFR-3 was expressed in usual lymphatics. Part of the tubular structures was connected to CD73(+) afferent lymphatics. These results indicate the presence and the importance of heterogeneous lymphatic microvasculature around sarcoid granulomas in pulmonary sarcoidosis.