Lymphangioleiomyomatosis: where endocrinology, immunology and tumor biology meet

Abstract

Lymphangioleiomyomatosis (LAM) is a cystic lung disease found almost exclusively in genetic females and caused by small clusters of smooth muscle cell tumors containing mutations in one of the two tuberous sclerosis genes (TSC1 or TSC2). Significant advances over the past 2-3 decades have allowed researchers and clinicians to more clearly understand the pathophysiology of LAM, and therefore better diagnose and treat patients with this disease. Despite substantial progress, only one proven treatment for LAM is used in practice: mTORC1 inhibition with medications such as sirolimus. While mTORC1 inhibition effectively slows LAM progression in many patients, it is not curative, is not effective in all patients, and can be associated with significant side effects. Furthermore, the presence of established and accurate biomarkers to follow LAM progression is limited. That said, discovering additional diagnostic and treatment options for LAM is paramount. This review will describe recent advances in LAM research, centering on the origin and nature of the LAM cell, the role of estrogen in LAM progression, the significance of melanocytic marker expression in LAM cells, and potential roles of the microenvironment in promoting LAM tumor growth. By appreciating these processes in more detail, researchers and caregivers may be afforded novel approaches to aid in the treatment of patients with LAM.

Lymphangioleiomyomatosis with Tuberous Sclerosis Complex—A Case Study

“…Many studies have shown that estrogen is an important factor in LAM cell proliferation, migration, and metastasis. Due to the coexpression of smooth muscle proteins (actin and desmin) and melanocyte markers (HMB-45, Melan-A, and MART-1), LAM cells are thought to derive from perivascular epithelial cells, although this is still unclear [1,9,14].…”

“…Disease progression occurs during periods with high estrogen concentrations, e.g., during pregnancy or hormonal therapy, while the development of symptoms declines after menopause. Some studies suggest that antiestrogen therapy could be a recognized treatment of LAM [1,7,14]. Reports on treatment with gestagens and estrogen receptor modulators are unclear and require further research.…”

Lymphangioleiomyomatosis (LAM) with Tuberous Sclerosis Complex - A Case Study

“…Many studies have shown that estrogen is an important factor in LAM cell proliferation, migration, and metastasis. Due to the co-expression of smooth muscle proteins (actin and desmin) and melanocyte markers (HMB-45, Melan-A, and MART-1), LAM cells are thought to derive from perivascular epithelial cells, although this is still unclear [1,8,11].…”

“…Patients with confirmed LAM should be treated with an mTOR inhibitor, sirolimus, or everolimus [2,11].…”

“…One of them is a gp100 premelanosomal protein, called PMEL. It is recognized by the HMB-45 antibody used to diagnose LAM [1,7,11].…”