Characterization of lymphatic malformations using primary cells and tissue transcriptomes

Abstract

Lymphatic malformations (LMs) are disfiguring congenital anomalies characterized by aberrant growth of lymphatic vessels. They are broadly categorized histopathologically as macrocystic and microcystic. Although sclerotherapy has shown some success in the treatment of macrocystic malformations, there has been less progress with developing treatment strategies for microcystic malformations. In this study, we characterized lymphatic endothelial cells isolated from lymphatic and lymphaticovenous malformations. When compared to cells from normal lymphatic vessels, we found that the primary cultured malformed cells are morphologically different and also exhibited differences in binding, proliferation, migration and tube formation. Transcriptome analysis identified several genes whose expression was substantially higher in malformed compared to normal lymphatic endothelium, including DIRAS3 and FOXF1. Further analysis of LM tissue samples revealed distinguishing gene expression patterns that could pave the way to understanding the molecular pathogenesis of LMs. Based on gene expression signatures, we propose a new hypothesis that the subtype of localized LMs could be formed because of disruptions in lymph node development.

Oral lymphatic malformations: A multicenter study of 208 cases and literature review

“…5,25 Most OLM cases become clinically evident until the age of two, but small and asymptomatic lesions may receive a later diagnosis. 3,5,6,12,14,21,22,27,39,43,44 Data from the multicenter study and the case report studies corroborate these findings, since children and adolescents presented larger OLMs than did adults or elderly individuals. This may also be the reason for such different mean ages among case series studies.…”

“…21,38 The literature has stated that LM has no sex or racial predilection. 3,5,6,15,39 Regarding OLM, two studies based on biopsy files had observed a female predilection, but both were conducted with a small sample. 31,40 By contrast, data from the present multicenter study and the literature review showed the absence of predilection for any sex.…”

“…1,2 Although some authors state that these lesions originate from an abnormal development of lymphatic vessels and the impossibility of binding the vessels to the venous system, recent studies have demonstrated the association of a postzygotic somatic mutation in gene PIK3CA with the pathogenesis of this condition. [3][4][5][6][7][8][9] The prevalence of LMs is approximately 1:5000 among live births. 10 The diagnosis can be made before the baby is born (in the womb), but most lesions are clinically recognized by the age of 2.…”

“…Lymphatic malformations (LMs), also known as lymphangiomas, are uncommon lesions that usually affect the head and neck regions 1,2 . Although some authors state that these lesions originate from an abnormal development of lymphatic vessels and the impossibility of binding the vessels to the venous system, recent studies have demonstrated the association of a postzygotic somatic mutation in gene PIK3CA with the pathogenesis of this condition 3–9 …”

Recent Progress in Lymphangioma

“…Another report identified that the genes encoding FOXF1 and DIRAS3 are highly overexpressed in LM-LECs ( 70 ). Haploinsufficiency of FOXF1and FOXC2 may be associated with macrocystic LM ( 71 ).…”