Comprehensive Evaluation of 35 Patients With Lymphangioleiomyomatosis

doi:10.1378/chest.115.4.1041

Chest

Volume 115, Issue 4, April 1999, Pages 1041-1052

https://doi.org/10.1378/chest.115.4.1041 Get rights and content

Objectives

To evaluate comprehensively the characteristics of lymphangioleiomyomatosis (LAM), with emphasis on the application of imaging and immunohistochemical methods.

Design

Prospective study.

Patients

Thirty-five female subjects with LAM.

Setting

Clinical Center, National Institutes of Health.

Interventions

BAL, pulmonary function test, ventilation/perfusion lung scans, CT of the chest and abdomen, ultrasonography of abdomen, and immunohistochemical study of lung biopsy specimens.

Results

Most patients had exertional dyspnea (83%) and pneumothorax (69%). BAL did not show diagnostic changes. The most common abnormalities on pulmonary function tests were decreased diffusing capacity of carbon monoxide (83%), hypoxemia (57%), and airway obstruction (51%). Bronchodilator response was found in 26% of patients. CT, which is almost pathognomonic, showed numerous thin-walled cysts throughout both lungs in all patients. Thirty-four patients (97%) had abnormal ventilation and/or perfusion lung scans. An unusual “speckling” pattern was observed on ventilation scans of 74% of patients. Common extrapulmonary features were retroperitoneal adenopathy (77%) and renal angiomyolipomas (60%). The percentage of abnormal smooth muscle cells (LAM cells), reactive with HMB45, varied from 17 to 67% in 10 lung biopsy specimens.

Conclusions

Improved diagnostic methods have defined the abnormalities in patients with pulmonary LAM and increased the potential for early recognition and treatment of this disorder. Patients with LAM should be evaluated for bronchodilator responsiveness and may benefit from a trial of bronchodilators.

Section snippets

Study Population

The study population consisted of 35 women with LAM who had not received lung transplants and did not have clinical stigmata of tuberous sclerosis such as facial angiofibroma, seizures, mental retardation, ungual fibromas, hypomelanotic macules, gingival fibroma, or a shagreen patch. These patients were evaluated at the Warren Grant Magnuson Clinical Center of the National Institutes of Health between 1995 and 1997. The study protocol was approved by the Institutional Review Board at the

Patient Characteristics

All 35 LAM patients studied were women. The mean age of the patients was 38.5 ± 8.0 years at the time of diagnosis and 42.3 ± 8.6 years (Table 1) at the time of entry into the study. The major manifestations that led to the diagnosis of LAM were exertional dyspnea (46%) and pneumothorax (43%).

Major symptoms or signs during the course of the disease were dyspnea (83%), pneumothorax (69%), and frequent cough (66%). The mean number of episodes of pneumothorax in patients with a history of this

Discussion

The present study provides a comprehensive report of the clinical features of LAM, including pulmonary and extrapulmonary involvement, with emphasis on diagnostic data derived from BAL, pulmonary function tests, ventilation/perfusion lung scans, high-resolution CT of chest and abdomen, and immunohistochemical study (HMB45 antibody) of lung tissue. These data complement those reported by Taylor et al¹ and Kitaichi et al² who paid particular attention to the clinical course and outcome of the

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Lymphangioleiomyomatosis (LAM) is a multisystem disease occurring in women of child-bearing age manifested by uncontrolled proliferation of smooth muscle–like “LAM” cells in the lungs. LAM cells bear loss-of-function mutations in tuberous sclerosis complex (TSC) genes TSC1 and/or TSC2, causing hyperactivation of the proliferation promoting mammalian/mechanistic target of Rapamycin complex 1 pathway. Additionally, LAM-specific active renin-angiotensin system (RAS) has been identified in LAM nodules, suggesting this system potentially contributes to neoplastic properties of LAM cells; however, the role of this renin-angiotensin signaling is unclear. Here, we report that TSC2-deficient cells are sensitive to the blockade of angiotensin II receptor type 1 (Agtr1). We show that treatment of these cells with the AGTR1 inhibitor losartan or silencing of the Agtr1 gene leads to increased cell death in vitro and attenuates tumor progression in vivo. Notably, we found the effect of Agtr1 blockade is specific to TSC2-deficient cells. Mechanistically, we demonstrate that cell death induced by Agtr1 inhibition is mediated by an increased expression of Klotho. In TSC2-deficient cells, we showed overexpression of Klotho or treatment with recombinant (soluble) Klotho mirrored the cytocidal effect of angiotensin blockade. Furthermore, Klotho treatment decreased the phosphorylation of AKT, potentially leading to this cytocidal effect. Conversely, silencing of Klotho rescued TSC2-deficient cells from cell death induced by Agtr1 inhibition. Therefore, we conclude that Agtr1 and Klotho are important for TSC2-deficient cell survival. These findings further illuminate the role of the RAS in LAM and the potential of targeting Agtr1 inhibition in TSC2-deficient cells.
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A diffuse lung disease (DLD) also known as interstitial lung disease (ILD) is a pathologic process in which it is not possible to localize unambiguously the topographic site of onset. The high-resolution computed tomography (HRCT) appearance of each disease depends on the elementary lesions and their distribution throughout the lung. If an abnormality is discovered, the subsequent step is dedicated to identifying its prevalent aspects, which in turn depend upon the underlying pathology. In the DLD universe, basic radiologic patterns play an important role in the beginning of the diagnostic assessment. According to the literature and based on the personal experience, the distinction of six main radiologic patterns is suggested: septal pattern, fibrotic pattern, nodular pattern, alveolar pattern, cystic pattern, and dark lung pattern. Therefore, we would suggest matching the above six HRCT patterns with the pathological ones in order to allow a pathologist to quickly understand what the radiological picture looks like on H&E. Some of the patterns completely match with each other and in most of the others it is easy describe. A solitary pulmonary nodule (SPN) is a round opacity of the lung less than 3 cm in diameter. To ensure that they are not malignant, a careful assessment should be done before establishing the optimal management: follow-up, biopsy, or surgery. The diagnostic process for SPNs develops through a decision analysis algorithm coupling the a priori probability of malignancy (risk factors) with the elements of the imaging, where CT is the standard basic imaging technique. An SPN may be solid or subsolid (pure ground-glass opacity or ground-glass opacity with solid component). CT has a higher sensitivity and specificity than chest radiography and gives extra information about the density of the nodule and its vascularization. Supplementary information about tumor metabolism can be further acquired by means of positron emission tomography.
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Lymphangioleiomyomatosis (LAM) is a slowly progressive, low-grade, metastasising neoplasm of women, characterised by infiltration of the lung parenchyma with abnormal smooth muscle-like cells, resulting in cystic lung destruction. The invading cell in LAM arises from an unknown source and harbours mutations in tuberous sclerosis complex (TSC) genes that result in constitutive activation of the mechanistic target of rapamycin (mTOR) pathway, dysregulated cellular proliferation, and a programme of frustrated lymphangiogenesis, culminating in disordered lung remodelling and respiratory failure. Over the past two decades, all facets of LAM basic and clinical science have seen important advances, including improved understanding of molecular mechanisms, novel diagnostic and prognostic biomarkers, effective treatment strategies, and comprehensive clinical practice guidelines. Further research is needed to better understand the natural history of LAM; develop more powerful diagnostic, prognostic, and predictive biomarkers; optimise the use of inhibitors of mTOR complex 1 in the treatment of LAM; and explore novel approaches to the development of remission-inducing therapies.

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Supported by Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.

No authors have any financial involvement in any organization with adirect financial interest in the subject discussed in this article.

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Chest

Clinical InvestigationsDiffuse Lung DiseaseComprehensive Evaluation of 35 Patients With Lymphangioleiomyomatosis

Objectives

Design

Patients

Setting

Interventions

Results

Conclusions

Section snippets

Study Population

Patient Characteristics

Discussion

Hum Pathol

J Urol

J Biol Chem

Clin Imaging

Chest

J Urol

Lymphangioleiomyomatosis: clinical course in 32 patients

N Engl J Med

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

Am J Respir Crit Care Med

Pulmonary lymphangiomyomatosis: a review

Am J Pathol

Lymphangioleiomyomatosis: new insights

Am J Respir Crit Care Med

Lung transplantation for lymphangioleiomyomatosis

N Engl J Med

Extrathoracic angiomyolipomas in lymphangioleiomyomatosis

Eur Respir J

How common are renal angiomyolipomas in patients with pulmonary lymphangiomyomatosis?

Am J Respir Crit Care Med

Angiomyolipomas in a case of lymphangiomyomatosis syndrome: relationships to tuberous sclerosis

Cancer

Basic fibroblast growth factor in human pheochromocytoma: a biochemical and immunohistochemical study

Int J Cancer

Pulmonary lymphangioleiomyomatosis: diagnosis based on results of transbronchial biopsy and immunohistochemical studies and correlation with high-resolution computed tomography findings

Arch Pathol Lab Med

Angiomyolipoma of the kidney: immunoreactivity with HMB-45: light- and electron-microscopic findings

Histopathology

Accurate quantification of cells recovered by bronchoalveolar lavage

Am Rev Respir Dis

Clinical Investigations
Diffuse Lung Disease
Comprehensive Evaluation of 35 Patients With Lymphangioleiomyomatosis