Zhang Chaonan, Liu Jing, Wang Yao, Zheng Yingying, Malashicheva Anna, Qi Li, Shi Xiaohong, Liu Ju
School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, P.R. China; Laboratory of Translational Medicine in Microvascular Regulation, Medical Research Center, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, P.R. China; Shandong Provincial Key Medical and Health Laboratory of Translational Medicine in Microvascular Aging, Jinan, Shandong, P.R. China; Laboratory of Future Industry of Gene Editing in Vascular Endothelial Cells of Universities in Shandong Province, Jinan, Shandong, P.R. China.
Laboratory of Translational Medicine in Microvascular Regulation, Medical Research Center, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, P.R. China; Shandong Provincial Key Medical and Health Laboratory of Translational Medicine in Microvascular Aging, Jinan, Shandong, P.R. China; Laboratory of Future Industry of Gene Editing in Vascular Endothelial Cells of Universities in Shandong Province, Jinan, Shandong, P.R. China.
Ann Vasc Surg. 2025 May 23;121:35-46. doi: 10.1016/j.avsg.2025.05.028.
Lymphatic malformation (LM) is a lymphatic system tumor caused by abnormal development during the embryonic period, which leads to structural defects in the lymphatic vessels. It originates from lymphatic endothelial cells (LECs) and is prone to occur in the lymphatic vessels of the head, neck and axilla. It is characterized by abnormal proliferation and cystic expansion of LECs. In the current study of the molecular mechanism of LM, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha and phosphoinositide-3-kinase regulatory subunit 3 gene mutations lead to abnormal activation of phosphatidylinositol 3-kinase/protein kinase B/Mammalian Target Of Rapamycin (mTOR) signaling pathway, promoting LM LECs proliferation, and lymphangiogenesis; vascular endothelial growth factor C (VEGF-C) binds to vascular endothelial growth factor receptor 3 (VEGFR-3) to promote the survival, proliferation, and migration of LECs. Overexpression of VEGF-C is involved in the formation of LM subtype gorham-stout disease; in the Wnt/β-catenin signaling pathway, wingless-type mouse mammary tumor virus integration site family member 5A loss leads to the occurrence of LM; asparaginyl-tRNA synthetase mutations activate extracellular signal-regulated kinase phosphorylation, driving the occurrence of LM subtypes generalized lymphatic abnormality and kaposiform lymphangiomatosis. Clinically, treatment strategies are symptom-oriented and individualized according to the location and clinical manifestations of the disease. In recent years, mTOR inhibitor sirolimus and VEGFR-3 inhibitors are effective in the treatment of LM. This review aims to explore the latest progress of clinical manifestations, pathogenesis, and treatment methods of LM.
淋巴管畸形（LM）是一种由胚胎期发育异常引起的淋巴系统肿瘤，导致淋巴管结构缺陷。它起源于淋巴管内皮细胞（LEC），易发生于头、颈和腋窝的淋巴管。其特征是LEC异常增殖和囊性扩张。在目前对LM分子机制的研究中，磷脂酰肌醇-4,5-二磷酸3-激酶催化亚基α和磷脂酰肌醇-3-激酶调节亚基3基因突变导致磷脂酰肌醇3-激酶/蛋白激酶B/雷帕霉素哺乳动物靶标（mTOR）信号通路异常激活，促进LM LEC增殖和淋巴管生成；血管内皮生长因子C（VEGF-C）与血管内皮生长因子受体3（VEGFR-3）结合，促进LEC的存活、增殖和迁移。VEGF-C的过表达参与了LM亚型戈尔曼-斯托特病的形成；在Wnt/β-连环蛋白信号通路中，无翅型小鼠乳腺肿瘤病毒整合位点家族成员5A缺失导致LM的发生；天冬酰胺-tRNA合成酶突变激活细胞外信号调节激酶磷酸化，驱动LM亚型泛发性淋巴管异常和卡波西样淋巴管瘤病的发生。临床上，治疗策略以症状为导向，并根据疾病的部位和临床表现进行个体化治疗。近年来，mTOR抑制剂西罗莫司和VEGFR-3抑制剂对LM的治疗有效。本综述旨在探讨LM的临床表现、发病机制和治疗方法的最新进展。
