Virchows Arch (2003) 443:17–27 DOI 10.1007/s00428-003-0824-0 ORIGINAL ARTICLE Hamdy Metwaly · Jun Cheng · Hiroko Ida-Yonemochi · Kazufumi Ohshiro · Kai Yu Jen · Ai Ru Liu · Takashi Saku Vascular endothelial cell participation in formation of lymphoepithelial lesions (epi-myoepithelial islands) in lymphoepithelial sialadenitis (benign lymphoepithelial lesion) Received: 7 January 2003 / Accepted: 7 April 2003 / Published online: 22 May 2003  Springer-Verlag 2003 Abstract Lymphoepithelial lesions (LELs, or epi-myo- epithelial islands) in lymphoepithelial sialadenitis (LESA, or benign lymphoepithelial lesion) of the salivary gland are known to be mainly composed of duct epithelial cells. However, other constituent cells are poorly characterized. Formalin-fixed paraffin sections obtained from six surgi- cal specimens of LESA were examined using immuno- histochemistry for cytoskeletal proteins, inflammatory cells, vascular endothelial cells, and extracellular matrix (ECM) molecules as well as by in situ hybridization for ECM molecules. In addition to keratin-immunopositive (+) duct-like epithelial cells, there were CD31/CD34+ vascular endothelial cells—which were either scattered in a singular fashion, in formed sheets, or in tubular structures—, CD20+ B lymphocytes, CD45RO+ T lym- phocytes, and CD68 macrophages in the LELs. ECM molecules, such as heparan sulfate proteoglycan and tenascin, were immunolocalized in hyaline materials in the LELs. Their mRNAs were demonstrated mainly in endothelial cells and, to a lesser extent, in lympho- monocytic cells around hyaline materials, but were not as evident in epithelial constituent cells of LELs. The results indicate that endothelial cells as well as inflammatory cells are important constituents of the LELs, and the hyaline ECM cores mainly result from the intra-LEL angiogenesis by endothelial cells with the assistance of inflammatory cells. This intra-LEL vasculature seems to support regeneration and proliferation of salivary epithe- lial remnant cells. Keywords Benign lymphoepithelial lesion · Endothelial cell · Epi-myoepithelial island · Lymphoepithelial lesion · Lymphoepithelial sialadenitis · Heparan sulfate proteoglycan Introduction Lymphoepithelial sialadenitis (LESA [13], also referred to as benign lymphoepithelial lesion [2, 9, 40, 41], lymphoepithelial lesion [3, 5, 18, 27, 30], myoepithelial sialadenitis (MESA) [10, 11], Sögren-type sialadenitis [15], or autoimmune sialadenitis [21, 22, 32]) of the salivary glands is histologically characterized by an extensive infiltration of chronic inflammatory cells replacing the salivary parenchymal space, which is composed of acinar and ductal cells. In their full-grown stages, ductal cell remnants regenerate to form epi- myoepithelial islands (EMIs), which sometimes show minimal ductal lumina but ultimately show solid epithe- lial nests. EMIs were first investigated using electron microscopy (EM) in the 1960s [2, 5, 9, 11, 19, 28, 32, 35, 40, 41] and were shown to be composed of both duct epithelial and myoepithelial cells. However, immunohis- tochemical studies for cytoskeletal proteins were intro- duced in this lesion in the 1980s, which indicated that cells with duct epithelial characteristics are mainly responsible for the EMI formation [3, 15, 16, 21, 22, 26, 27, 32, 38]. In addition to the EM studies, these immunohistochemical studies have also indicated that the EMIs are composed of not only epithelial cells but also of other inflammatory cells, as not all of the constituent cells of EMIs are immunolabeled for epithelial cytoskeletal proteins. Because of the negligible contribution of myoepithelial cells to the island formation, the usage of the term EMIs has been questioned, and pathologists have H. Metwaly · J. Cheng · H. Ida-Yonemochi · K. Ohshiro · K. Y. Jen · T. Saku ( ) ) Division of Oral Pathology, Department of Tissue Regeneration and Reconstruction, Niigata University Graduate School of Medical and Dental Sciences, 2-5274 Gakkocho-dori, 951-8514 Niigata, Japan e-mail: tsaku@dent.niigata-u.ac.jp Tel.: +81-25-2272832 Fax: +81-25-2270805 A. R. Liu Department of Oral Pathology, School of Stomatology, Shanghai Second Medical University, China