Structural Basis for Hyperpermeability of Tumor Vessels in Advanced Lung Adenocarcinoma Complicated by Pleural Effusion

BackgroundMalignant pleural effusion (MPE) has a profound impact on quality of life and survival in patients with lung cancer. Identification of the factors within the tumor and its environment that mediate MPE is still lacking.Patients and MethodsIntratumoral microvessel density (MVD), endothelial cell and pericyte (PC) capillary coverage, endothelial cell (EC)-PC relationship, lymphatic endothelium integrity, and the expression of receptor tyrosine kinases were all assessed immunohistochemically in pleural tumor biopsy specimens from 24 patients with lung adenocarcinoma (ADC) with and without pleural disease, with the aim to evaluate the involvement with MPE.ResultsIn the effusion-positive (⁺) specimens, MVD values were found to be significantly higher, and a number of vessels were noted to lack immunoreactivity for ECs (CD31). Likewise, PC α–smooth muscle actin (αSMA) expression was also less extensive in the MPE⁺ cases. The observation of only sporadic staining of PCs can also explain the findings regarding platelet-derived growth factor receptors (PDGFRs), the expression of which, although more prominent in MPE⁺ samples, were almost exclusively detected on tumor stromal cells and not on vascular PCs. Conversely, vascular endothelial growth factor receptors (VEGFRs) appeared on both kinds of cells. With respect to lymphatic vessels, lymphatic intraluminal tumor cells were occasionally found in MPE⁺ specimens.ConclusionOur study suggests that disturbed vessel wall integrity, as well as abnormalities of fluid clearance by the lymphatic system, together with overexpression of growth factors, may take part in the pleural fluid accumulation in lung ADCs. Results of the decreased PC capillary coverage and PDGFR expression in MPE are discussed.