Immunohistochemical Study of mTOR Pathway Activation in Lymphangioleiomyomatosis
L Gao, C Gong, N Schuger, L Schuger. University of Chicago, Chicago, IL
Background: Lymphangioleiomyomatosis (LAM) is a rare and fatal lung disease affecting women in their reproductive age. LAM is characterized by proliferation of infiltrative smooth muscle (SM)-like cells that lead to cystic destruction of the lung and eventually respiratory insufficiency. Tuberous Sclerosis Complex 1 and 2 (TSC1/TSC2, also known as hamartin and tuberin) form a tumor suppressor dimer that negatively regulates the mammalian target of rapamycin (mTOR)/S6K1 signaling pathway. Since LAM occasionally develops in the background of tuberous sclerosis (TS) and since tsc2 functional mutations and loss of heterozigosity (LOH) have been found in the lesions of several patients with sporadic LAM, it is currently believed that the disease is caused by lack of functional tuberin. To better understand the role of TSC1/TSC2/mTOR/S6K1 pathway in LAM, we applied IHC to determine whether there is a correlation between presence and level of tuberin, hamartin, phosphorylated mTOR and phosphorylated S6K1 kinase.
Design: Eight sporadic and one TS-associated LAM cases were included in this study. FFPE sections from diagnostic wedge biopsies were immunostained with antibodies against SM actin and HMB45 (LAM markers), tuberin, hamartin, phosphorylated mTOR and S6K1 antibodies. Tissue array sections and normal lung were used as external controls. The immunostaining intensity of LAM lesions and normal lung tissue was classified from +++ (strongest) to - (negative).
Results: Normal lung parenchyma and all sporadic LAM lesions immunostained for tuberin and hamartin. The lung sample from the TS case was entirely negative for tuberin and positive for hamartin. In LAM lesions tuberin and hamartin immunoreaction was either focal or diffuse and of intermediate in intensity (+/++), but diffuse and strong in reactive epithelial and mesothelial cells (+++) and negative (-) in blood vessels. In five sporadic cases and the TS-associated case, the LAM lesions were focally and weakly positive for phosphorylated mTOR (+) and/or S6K1 (+). In the other three sporadic cases the LAM lesions were negative for both. Epithelial and mesothelial cells were strongly positive for both (+++) and blood vessels were negative (-).
Conclusions: Tuberin and hamartin were present in the lesions of sporadic LAM, but the TS-associated case lacked tuberin altogether. There was weak mTOR pathway activation in 5 cases and no activation at all in 3 cases. A weak but protracted activation of the mTOR pathway may contribute to the pathogenesis of LAM in some cases, while it does not seem to play a role in others.
Monday, March 22, 2010 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 232, Monday Morning