ABSTRACT
Overactivation of the PI3K/AKT/mTOR or the RAS/MAPK/MEK pathway leads to dysregulation of normal cellular functions, resulting in cellular proliferation, survival advantage, and angiogenesis and is thought to be the driver for the development and/or progression of lymphatic and other vascular anomalies. Somatic mutations that lead to inappropriate activation of the PI3K/AKT/mTOR pathway have been shown to result in tissue overgrowth in association with vascular anomalies. Sirolimus is a specific and potent inhibitor of mTOR, a serine/threonine kinase in the PI3K/AKT pathway that regulates cellular catabolism and anabolism, cell motility, angiogenesis, and cell growth. Drug responsiveness to sirolimus has been reported in the majority of patients with lymphatic malformation, both micro- and macrocystic. Complex lymphatic malformations also appear to respond favorably to mTOR inhibition.
