Recent advances in understanding the pathogenesis, diagnosis, and treatment of tuberous sclerosis complex (TSC)-associated Lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a rare, slowly progressive lung disorder that predominantly affects women of childbearing age. LAM is classified into two subtypes: tuberous sclerosis complex (TSC)-associated LAM (TSC-LAM) and sporadic LAM. Mutations in the TSC1 or TSC2 genes are the underlying cause of both forms. Over the past decade, research and clinical practice in managing LAM have advanced significantly, with breakthroughs in the understanding of disease pathogenesis, biomarker discovery, targeted therapies, and new therapeutic technologies. This article presents a review of the progress in understanding the pathobiology, diagnosis, and treatment of LAM, based on PubMed-indexed studies published from 2015 to 2024. According to the current literature, the activation of mechanistic target of rapamycin (mTOR) signaling is the leading cause of LAM, while other mTOR-independent pathways, such as the sphingosine kinase 1 (SPHK1)/sphingosine-1-phosphate (S1P) and cyclooxygenase 2 (COX2)/prostaglandin E2 (PGE2) pathways, have been hypothesized to play roles in the pathogenesis. The literature suggests that LAM might originate in the uterine and/or pulmonary mesenchymal cells. Advanced imaging methods such as chest high-resolution CT (HRCT) and newly identified LAM biomarkers can aid in improving the diagnostic of LAM. mTOR inhibitors, such as sirolimus, remain the cornerstone therapy, but variable treatment responses highlight the need for personalized approaches. Nevertheless, more studies are needed to better understand LAM, develop more powerful diagnostic, prognostic, and predictive biomarkers, and optimize the current treatments of LAM while developing novel therapeutic approaches.