Lymphangioleiomyomatosis Lesions Research Articles

A Case of Pulmonary Lymphangioleiomyomatosis Developing 3 Years After Complete Surgical Removal of Abdominal Lymphangioleiomyoma

Abstract: Pulmonary lymphangioleiomyomatosis (LAM) is a rare disease that affects almost exclusively women, usually in childbearing age. LAM is usually mistaken for other common pulmonary diseases like asthma, bronchitis, or chronic interstitial lung diseases. We present a woman who developed pulmonary LAM after complete surgical removal of abdominal lymphangioleiomyoma 3 years earlier. Chest computed tomography at time of surgery did not show evidence of pulmonary involvement. LAM cells have the ability to proliferate and migrate to distant sites. Thus, pulmonary LAM is thought by many authors to originate from remote sites such as abdominal lymphangioleiomyomas and angiomyolipomas. Few reports in the past have documented the occurrence of pulmonary LAM 2 to 3 years after the excision of abdominal LAM lesions; however, the excision was not complete in these cases. Our case report may suggest that complete surgical removal of abdominal lymphangioleiomyoma may not prevent the development of pulmonary LAM or halt its progression. The issue of occurrence of pulmonary LAM after complete excision of extrapulmonary LAM lesions needs to be further elucidated to better define the clinical behavior of this disease.

Lymphangiogenesis-Mediated Shedding of LAM Cell Clusters as a Mechanism for Dissemination in Lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) affects exclusively women of reproductive age, involves the lungs and axial lymphatic system, and is frequently complicated with renal angiomyolipomas. LAM lesions are generated by the proliferation of LAM cells with mutations of one of the tuberous sclerosis complex (TSC) genes. Recent studies indicate that LAM cells can migrate or metastasize to form new lesions in multiple organs, although they show a morphologically benign appearance. In the previous study, we reported LAM-associated lymphangiogenesis and implicated its role in the progression of LAM. In this study, we further focused on the lymphatic abnormalities in LAM: LAM-associated chylous fluid (5 pleural effusion and 2 ascites), surgically resected diaphragm (1 patient), and axial lymphatic system including the thoracic duct, lymph nodes at various regions, and diaphragmatic lymphatic system (5 autopsy cases). We demonstrated that LAM cell clusters enveloped by lymphatic endothelial cells (LCC) in all chylous fluid examined. We identified LAM lesion in the diaphragm (2 of 5 autopy cases and one surgical specimen), thoracic duct (5 of 5), and lymph nodes (retroperitoneal (5 of 5), mediastinal (4 of 5), left venous angle (5 of 5) with total positive rate of 68% to 88% at each region of the lymph node, but less frequent or none at remote lymph nodes located away from the axial lymph trunk (cervical [1 of 5] and axillary [0 of 5]). LCCs were identified in intra-LAM lesional lymphatic channels where LAM cells proliferate along lymphatic system. In in vitro culture system, LCC can fragment into each proliferating LAM cell. These findings suggest that LAM-associated lymphangiogenesis demarcates LAM lesion into bundle- or fascicle-like structure and eventually shed LCC into the lymphatic circulation and that LCCs play a central role in the dissemination of LAM lesion.

Molecular and genetic analysis of disseminated neoplastic cells in lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM) is a multisystem disorder of women, characterized by cystic degeneration of the lungs, renal angiomyolipomas (AML), and lymphatic abnormalities. LAM lesions result from the proliferation of benign-appearing, smooth muscle-like LAM cells, which are characterized by loss of heterozygosity (LOH) of one of the tuberous sclerosis complex (TSC) genes. LAM cells are believed to migrate among the involved organs. Because of the apparently metastatic behavior of LAM, we tried to isolate LAM cells from body fluids. A cell fraction separated by density gradient centrifugation from blood had TSC2 LOH in 33 of 60 (55%) LAM patients. Cells with TSC2 LOH were also found in urine from 11 of 14 (79%) patients with AML and in chylous fluid from 1 of 3 (33%) patients. Identification of LAM cells with TSC2 LOH in body fluids was not correlated with severity of lung disease or extrapulmonary involvement and was found in one patient after double lung transplantation. These studies are compatible with a multisite origin for LAM cells. They establish the existence of disseminated, potentially metastatic LAM cells through a relatively simple, noninvasive procedure that should be valuable for molecular and genetic studies of somatic mutations in LAM and perhaps other metastatic diseases.

Imbalanced Plasminogen System in Lymphangioleiomyomatosis

Pulmonary lymphangioleiomyomatosis (LAM) is characterized by abnormal smooth muscle-like cell (LAM cell) proliferation leading to tissue destruction. We previously demonstrated that serum response factor (SRF), a critical smooth muscle transcription factor, is highly expressed in LAM cells. Here we show that a high SRF level alters the plasminogen (Plg) system. Specifically, overexpression of SRF in human lung fibroblasts upregulated urokinase-type plasminogen activator (uPA) and its substrate Plg, whereas it downregulated plasminogen activator inhibitor (PAI)-1. Because uPA cleaves Plg into plasmin, which activates matrix metalloproteinases (MMP), the end result was an increase in MMP activity. To determine whether uPA, Plg, and PAI-1 were abnormally expressed in LAM in vivo, we immunostained 12 LAM cases. In all cases, the LAM lesions showed stronger immunoreaction for uPA and Plg than the surrounding normal lung parenchyma. On the contrary, PAI-1 was absent in LAM lesions, whereas it was ubiquitous in normal lung parenchyma. Microdissection-based reverse transcriptase/polymerase chain reaction further confirmed upregulation of uPA and Plg and downregulation of PAI-1 message in LAM. Altogether, our findings suggest that the high SRF level seen in LAM contributes to extracellular matrix degradation and progressive LAM cell infiltration of the lung.

Tissue inhibitor of metalloproteinase-3 downregulation in lymphangioleiomyomatosis: potential consequence of abnormal serum response factor expression.

Pulmonary lymphangioleiomyomatosis (LAM) is characterized by abnormal smooth muscle-like cell proliferation leading to tissue destruction and cyst formation. We demonstrate that serum response factor (SRF), a critical smooth muscle transcription factor, is overexpressed in LAM cells. To determine whether abnormal SRF levels might have a pathogenic role in LAM, we transfected SRF into mouse lung fibroblasts and performed a cDNA array analysis. High SRF level upregulated the expression of matrix metalloproteinase (MMP)-2 and MMP-14, two MMPs previously shown to be increased in LAM. In addition, SRF down-regulated tissue inhibitor of metalloproteinase (TIMP)-3, one of their inhibitors. TIMP-3 inhibition was further confirmed by reverse transcriptase/polymerase chain reaction, immunoblotting, and immunostaining of human lung fibroblasts transfected with SRF fused to DsRed2 (a red variant of green fluorescent protein). To determine the in vivo significance of our findings, we immunostained 12 LAM cases for TIMP-3. In eight of them, TIMP-3 was ubiquitously present in normal lung parenchyma, but it was absent in LAM lesions. In the remaining cases, including two out of five normal control lungs, the antibody immunoreacted exclusively with elastin, probably due to suboptimal tissue processing. Because timp-3-null mice develop spontaneous emphysema, our findings suggest that SRF-mediated TIMP-3 inhibition might contribute to the tissue damage seen in LAM.

Recurrence of lymphangioleiomyomatosis after single lung transplantation: New insights into pathogenesis

Lymphangioleiomyomatosis (LAM) is a rare disease found primarily in white women of childbearing age. The present study describes a case of recurrent LAM after single lung transplantation. Double-staining nonisotopic in situ hybridization, immunohistochemistry, and short tandem repeat loci analysis demonstrated that the recurrent LAM lesions originated from the recipient. The data strongly support that metastatic spread of LAM cells or migration of progenitor cells plays an important role in the pathogenesis of LAM. HUM PATHOL 34:95-98. Copyright 2003, Elsevier Science (USA). All rights reserved.

Linfangioleiomiomatosis pulmonar (LAM). Utilidad diagnóstica de los marcadores inmunohistoquímicos

Lymphangioleiomyomatosis (LAM) is a rare disease of unknown cause affecting the lungs of female patients. Although clinical and radiological findings may suggest LAM, a firm diagnosis is usually made after lung biopsy. Cases of LAM (histochemical diagnosis) or "suggestive of LAM" at the "12 of October" Hospital are reviewed. We applied a battery of immunohistochemical tests not used to date--involving estrogen, progesterone, desmin and HMB45 receptors--that allowed us to classify specimens as having either LAM lesions or lesions with non-LAM muscle proliferation. Smooth muscle proliferation in LAM is a distinct phenotype, such that diagnosis is facilitated by analyzing for immunohistochemical markers such as HMB45. This marker can be detected on formalin-fixed paraffin-embedded sheets in specimens obtained by either open lung or transbronchial biopsy.

Pulmonary lymphangioleiomyomatosis: a report of 46 patients including a clinicopathologic study of prognostic factors.

The clinical and pathologic features of 46 patients from Japan, Korea, and Taiwan with pulmonary lymphangioleiomyomatosis (LAM) were studied. Only two (5%) among 40 evaluable treatments were assessed to be effective. Some prognostic factors of LAM were recognized. A reduction of the forced expiratory volume in one second/forced vital capacity (FEV1/FVC) ratio was a poor prognostic factor at 2 yr after the first examination, with a statistically significant difference (p < 0.05). An increase in the percentage of predicted total lung capacity (%TLC) correlated with a poor prognosis at 2, 3, and 5 yr after the first examination, with statistically significant differences (p < 0.05). Histologically, two types of pulmonary lesions were observed; a predominantly cystic type and a predominantly muscular type. Patients with predominantly cystic LAM lesions showed a tendency to a poor prognosis from 2 to 5 yr after the biopsy. Among open lung biopsy findings, higher grades of abnormal areas were unfavorable as a prognostic factor from 2 to 5 yr after the biopsy, with statistically significant differences (p < 0.05). Higher grades of cystic lesions correlated inversely with survival at 2, 4, and 5 yr after the lung biopsy, with statistically significant differences (p < 0.05).