Schematic overview of the RAS/MAPK and PI3K/AKT LEC signal transduction pathways involved in LM and CLAs (GSD, KLA, CCLA, and GLA). Activating and inactivating mutations in disease-causative proteins have been indicated. Lines ending with arrowheads indicate positive regulations, and lines ending with bars indicate inhibitory regulations of substrate proteins. A somatic activating PIK3CA (encoding PI3Kα) mutation in LECs leads to a cell-autonomous increase in PI3K/AKT signaling as well as LEC proliferation and migration and can be targeted with PI3K pathway inhibitors, including alpelisib (targeting PI3Kα, currently in clinical trials for LM treatment), miransertib (targeting AKT), and rapamycin (targeting mTOR, also currently in trials for LM treatment). RAS/MAPK pathway activating mutations mainly found in GSD, KLA, and CCLA can be targeted with the MEK inhibitor trametinib (blue). Paracrine signaling between mutant LECs and stromal cells contributes to pathological vascular growth, potentially offering additional therapeutic options. For example, infiltration of VEGF-C–producing macrophages, which is actively driven by LECs, promotes pathological Pik3ca-driven lymphatic overgrowth that can be inhibited by VEGF-C blockade or antiinflammatory COX2 inhibition in mice (51). Antiinflammatory properties of rapamycin may contribute to its beneficial effects in limiting LM growth. LM, lymphatic malformation; GLA, generalized lymphatic anomaly; KLA, Kaposiform lymphangiomatosis; GSD, Gorham-Stout disease; CCLA, central conducting lymphatic anomaly; TLO, tertiary lymphoid organ composed of lymphocytes (blue), macrophages (red), and specialized high endothelial venules (gray).