Lymphatic Malformation: Classification, Pathogenesis, and Therapeutic Strategies

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.