Cytologic, Immunocytochemical and Ultrastructural Characterization of Lymphangioleiomyomatosis Cell Clusters in Chylous Effusions of Patients with Lymphangioleiomyomatosis
“…[18][19][20] VEGF-D has also been implicated in LAM cell proliferation via the Akt/mTOR pathway. 21 We speculate that VEGF-D promotes metastasis in LAM and that therapeutic strategies that target lymphangiogenic pathways have promise.…”
L ymphangioleiomyomatosis (LAM) is a rare, progressive, frequently fatal cystic lung disease that affects women almost exclusively. 1,2 LAM occurs in up to 40% of women with tuberous sclerosis complex (TSC-LAM), 3-5 a tumor suppressor syndrome associated with seizures, cognitive impairment, and hamartomas in multiple organs, and in a nonheritable sporadic form (S-LAM) that involves only the lung,
“…[18][19][20] VEGF-D has also been implicated in LAM cell proliferation via the Akt/mTOR pathway. 21 We speculate that VEGF-D promotes metastasis in LAM and that therapeutic strategies that target lymphangiogenic pathways have promise.…”
L ymphangioleiomyomatosis (LAM) is a rare, progressive, frequently fatal cystic lung disease that affects women almost exclusively. 1,2 LAM occurs in up to 40% of women with tuberous sclerosis complex (TSC-LAM), 3-5 a tumor suppressor syndrome associated with seizures, cognitive impairment, and hamartomas in multiple organs, and in a nonheritable sporadic form (S-LAM) that involves only the lung,
“…20 Th e disease phenotype is associated with lung nodules infi ltrated with lymphatics, lymphatic vessels showing LAM cells penetrating through the walls, and chylous eff usions. [19][20][21][22][23][24][25] Th ese forms of LAM are characterized by the presence of vascular abnormalities and evidence of arteriolar and venular channels as well as lymphatic channel infi ltration by LAM cells, resulting in both vascular obstruction and vascular wall disruption. 6,18 In the lungs, the consequences of these abnormalities are twofold.…”
Section: Discussionmentioning
confidence: 99%
“…6,18 LAM cell clusters (LCCs) have been noted in chylous eff usions and elsewhere. 19 Th ese LCCs consist of LAM cells surrounded by lymphatic endothelial cells. 19,20 LCCs are present in lung lymphatics, lymph nodes, uterus, and chylous fl uid.…”
mentioning
confidence: 99%
“…19 Th ese LCCs consist of LAM cells surrounded by lymphatic endothelial cells. 19,20 LCCs are present in lung lymphatics, lymph nodes, uterus, and chylous fl uid. 19,20 LAM cells infi ltrate and penetrate the lymphatic channels and pulmonary arterioles, leading to leakage of chyle and blood.…”
mentioning
confidence: 99%
“…19,20 LCCs are present in lung lymphatics, lymph nodes, uterus, and chylous fl uid. 19,20 LAM cells infi ltrate and penetrate the lymphatic channels and pulmonary arterioles, leading to leakage of chyle and blood. 6,18,20 Occlusion or infi ltration of pulmonary arterioles by LAM cells may account for the hemoptysis described by patients with LAM.…”
BACKGROUND: Lymphangioleiomyomas occur in 38% of patients with sporadic lymphangioleiomyomatosis (LAM) and may cause pain and increased abdominal girth, mimicking the presence of a malignancy. Lymphatic involvement in LAM is closely associated with elevated serum levels of vascular endothelium growth factor-D (VEGF-D). Because lymphangioleiomyomas undergo diurnal variation in volume, we hypothesized that daytime ingestion of food, by increasing chyle formation and lymphatic fl ow, is the cause of an increase in lymphangioleiomyoma volume.
Lymphangioleiomyomatosis (LAM) is a rare multisystem disease with a variable clinical course. The lungs are infiltrated by nodules of LAM cells, stromal cells and inflammatory cells, causing lung cysts and respiratory failure. We used immunohistochemical markers in lung biopsy and transplant samples from a national cohort of women with LAM with linked clinical data to understand how LAM nodule cell populations changed with disease progression. Marker distribution was examined qualitatively by dual immunohistochemistry, and markers for LAM cells, fibroblasts, lymphatics, mast cells, proliferation, cathepsin K and mTOR pathway activity were quantitated in LAM nodules and compared with clinical features and prospective lung function loss. The LAM cell marker PNL2 was more extensively expressed in those with higher forced expiratory volume in one second (FEV
1
), higher diffusion in the lung for carbon monoxide (DL
CO
) and less extensive disease involvement whilst the converse was true for the protease cathepsin K. Each percentage increase in cathepsin K reactivity was associated with a 0.65% decrease in FEV
1
(95% CI −1.11 to −0.18) and a 0.50% decrease in DL
CO
(95% CI −0.96 to −0.05). Higher reactivity to the mTOR complex 1 activation marker, phospho‐ribosomal protein S6, was associated with a better lung function response to rapamycin (
p
= 0.0001). We conclude that LAM nodules evolve with disease progression, with LAM cells becoming outnumbered by fibroblasts. Increasing cathepsin K expression is associated with more severe disease and lung function loss. Markers of mTOR activation predict the response to rapamycin, suggesting that more advanced LAM may be less mTOR responsive and treatments specifically targeted towards LAM associated fibroblasts may have roles as adjuncts to mTOR inhibition.
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