Intussusceptive Lymphangiogenesis in Lymphatic Malformations/Lymphangiomas

Abstract

Intussusception in lymphatic vessels has received less attention than in blood vessels. In tumors and pseudotumors of blood vessels with intravascular papillary structures, including sinusoidal hemangioma and intravascular papillary endothelial hyperplasia, we observed exuberant intussusceptive angiogenesis, as well as the similarity between papillae (term used by pathologists) and pillars/folds (hallmarks of intussusceptive angiogenesis). A similar response could be expected in lymphangiomas (lymphatic malformations and reactive processes rather than tumors) with papillae. The aim of this work is to assess whether papillae/pillars/folds and associated structures (vessel loops and septa) are present in lymphangiomas, and to establish the characteristics and formation of these structures. For this purpose, we selected lymphangiomas with intraluminal papillae (n = 18), including cystic, cavernous, circumscriptum, and progressive types, of which two cases of each type with a greater number of papillae were used for serial histologic sections and immunohistochemistry. The studies showed a) dilated lymphatic spaces giving rise to lymphatic-lymphatic vascular loops, which dissected and encircled perilymphatic structures (interstitial tissue structures/ITSs and pillars/posts), b) ITSs and pillars, surrounded by anti-podoplanin-positive endothelial cells, protruding into the lymphatic spaces (papillary aspect), and c) splitting, remodeling, linear arrangement, and fusion of papillae/pillars/folds, forming papillary networks and septa. In conclusion, as occurs in blood vessel diseases, the development of lymphatic vessel loops, papillae/pillars/folds, and septa (segmentation) supports intussusceptive lymphangiogenesis and suggests a piecemeal form of intussusception. This intussusceptive lymphangiogenesis in lymphatic diseases can provide a basis for further studies of lymphatic intussusception in other conditions, with clinical and therapeutic implications.

Participation of Intussusceptive Angiogenesis in the Morphogenesis of Lobular Capillary Hemangioma

“…www.nature.com/scientificreports www.nature.com/scientificreports/ This work and previous studies 14,16 show that LCH, sinusoidal hemangioma and IPEH present different morphologic patterns and share hallmarks of intussusception, in which vessel loops have an important morphogenic role. A similar participation of vessel loops has been demonstrated in the ovarian vein of the rat after ovariectomy and human tumour xenograft implantation 10,11 and in other human blood and lymphatic vessel diseases, such as hemorrhoidal disease, lymphangiomas/lymphatic malformations and vascular transformation of lymph node sinuses, as well as in some sinuses of developing human foetal lymph nodes 5,14,[27][28][29] . We use the term "piecemeal form of intussusceptive angiogenesis" to describe the mechanism of the formation and intravascular transport of pillars by vessel loops 5,[14][15][16]30 .…”

Adipose-Derived Stem Cells Promote Intussusceptive Lymphangiogenesis by Restricting Dermal Fibrosis in Irradiated Tissue of Mice

“…These advantages are reasonable if intussusceptive lymphangiogenesis occurs in the lymphedema region. Intussusceptive lymphangiogenesis, as a mechanism, is reported in lymphatic malformation/lymphangiomas and sinuses of developing human fetal lymph nodes [57,58]. Díaz-Flores et al suggested a possible molecular mechanism of intussusceptive lymphangiogenesis in the developing lymph node by which a high abundance of VEGF-C whole lymph node cells, without VEGF-C gradient, results in the nonsprouting engulfment of the lymph node anlage by LECs [57].…”

Comparison of the Behavior of Perivascular Cells (Pericytes and CD34+ Stromal Cell/Telocytes) in Sprouting and Intussusceptive Angiogenesis

“…Pericytes participate in intravascular pillar formation, contributing to vascular division by intussusception. The timing of pericyte incorporation into the pillar depends on the mechanism of pillar formation by (a) the establishment of endothelial contacts between opposite vessel walls and interendothelial bridge development, (b) pillar splitting, (c) the merging of adjacent capillaries and modifications of contacting walls, (d) the incorporation into pre-existing vessels of the interstitial structures surrounded by patent vessel loops formed by sprouting angiogenesis from these pre-existing vessels, (e) thrombus fragments or microthrombi originating transitional cores covered by reoriented ECs from the vessel wall, and (f) combinations of some of these mechanisms [ 26 , 39 , 41 , 45 , 46 , 200 , 201 , 202 ].…”