Pulmonary Lymphangioleiomyomatosis

1 REVIEW ARTICLE Pulmonary Lymphangioleiomyomatosis* 1 2 PEDRO MEDEIROS JUNIOR , CARLOS ROBERTO RIBEIRO DE CARVALHO Lymphangioleiomyomatosis (LAM) is a rare lung disease of unknown etiology that primarily affects women of childbearing age. Clinically, it manifests as progressive dyspnea, hemoptysis, pneumothorax and chylous pleural effusion resulting from abnormal smooth muscle proliferation in the lung parenchyma, lymph nodes, small airways and blood vessels. Recent cytogenetic studies have disclosed mutations of the tuberous sclerosis complex (TSC)-2 gene in cells of renal angiomyolipoma and in abdominal lymph nodes, pointing to hamartomatous lesions as a possible etiology. Chest radiography may appear normal or yield reticulonodular infiltrates and signs of hyperinflation. In high-resolution computed tomography scans, multiple thin-walled cysts can be seen throughout the lung parenchyma. Abdominal imaging by either ultrasound or computed tomography may show renal angiomyolipomas and retroperitoneal lymph node enlargement. Meningiomas may be seen concomitantly, requiring that testing for TSC be performed. Physiologically, LAM is characterized by progressive airflow obstruction, air trapping and gas-transfer impairment. Estrogenic suppression with either oophorectomy, deposit progestogens, tamoxifen and gonadotropin-releasing hormone analogs, is still the primary treatment. In addition to this therapy, lung transplants have increased patient median survival rates by more than ten years. Key words: Lymphangiomyomatosis/etiology. Lung neoplasms. * Studied carried out in the Pulmonology Department of the Faculdade de Medicina da Universidade de São Paulo (FMUSP). 1. Preceptor for the Pulmonology Department 2. Tenured Associate Professor in the Pulmonology Department Correspondence to: Pedro Medeiros Junior R. Alves Guimarães 408 Apt 164 – Jardim América – Cep: 05410000 São Paulo – SP; Telefone: 0xx11- 3081-4401; Fax: 3069-7202; e-mail: Submitted: 25/06/2003. Accepted, after revision: 15/09/2003 Abbreviations used in this paper: LAM – Lymphangioleiomyomatosis TPR – Total pulmonary resistance CO – Carbon monoxide DLCO – Diffusion capacity for carbon monoxide TS – Tuberous sclerosis TSC – Tuberous sclerosis complex GnRH – Gonadotropin-releasing hormone COPD – Chronic obstructive pulmonary disease ACE – Angiotensin-converting enzyme HRT – Hormone replacement therapy PCNA – Proliferating cell nuclear antigen MMP – Matrix metalloproteinase MT1-MMP – Membrane-type 1 matrix metalloproteinase HMB-45 α-SMA – Anti-melanoma monoclonal antibody – α-smooth muscle actin FEV1 – Forced expiratory volume in one second CNS – Central nervous system FSH – Follicle stimulating hormone LH – Luteinizing hormone HX – Histiocytosis X HRCT – High resolution computed tomography 2 INTRODUCTION Historical considerations From 1937 to 1955, 3 papers were published reporting cases of women who all presented with chylothorax, mediastinal lymph node enlargement, and pulmonary cystic lesions combined with pneumothorax.(1,2,3) In 1956, Cornog and Enterline(4) reviewed 45 cases in which the findings were very similar to those from the previous cases and designated this condition pulmonary lymphangiomatosis syndrome. Although the initial reports questioned the malignant potential of the disease (dissemination through the lymph vessels), Cornog and Enterline believed that the absence of cellular atypia and of significant mitotic activity, together with the degree of organization of the pulmonary lesions, disproved that hypothesis. They also believed that this process was attributable to a single agent, possibly of genetic origin, which acts on smooth muscle fibers in the lungs and lymph nodes. It was then characterized as a new clinical disease, which was restricted to women of childbearing age and, therefore, likely mediated by hormones. EPIDEMIOLOGY The reported prevalence of pulmonary lymphangioleiomyomatosis (LAM) is about 1/1,000,000 in Great Britain,(5) France(6) and the United States(7). However, prevalence must be higher, especially because very little is known about the disease, which delays its diagnosis. A recent survey among Canadian pulmonologists revealed that, of 118 physicians, 61 had never encountered a case of LAM. However, various reports have been published (about 300 cases registered in the literature), indicating that the global incidence is approximately 100 cases a year(7). In Brazil, a study is ongoing in the pulmonology departments of the FMUSP Hospital das Clínicas, the Hospital São Paulo and the Hospital do Sevidor Público Estadual, in which 37 patients have been diagnosed with LAM since 1982. Of those 37, 24 are still living and are being monitored. PATHOLOGY A progressive cystic transformation throughout the lung parenchyma is a characteristic finding in patients with LAM. These changes seem to basically appear from the proliferation of atypical smooth muscle cells around the bronchiole structure, which results in airflow obstruction and lesions in the alveolar space, leading to pulmonary collapse. Many patients may also present with subpleural bullae. Muscular proliferation involving venules may cause primary pulmonary hypertension and obstruction of venous blood flow.(29) Evaluation of the lesions reveals that the pulmonary architecture is progressively altered by the proliferation of atypical smooth muscle cells around bronchioles, blood vessels, and lymph nodes. According to Bionetti et al.,(30) there seem to be 3 distinct cellular forms: large fusiform cells, small fusiform cells, and epithelioid cells (Figure 1). These cellular types present distinct immunophenotypes and, according to the findings of Matsui et al.,(31) also have distinct roles in the pathogenesis of pulmonary lesions. In this study, we analyzed lung tissues obtained from 5 patients before and after therapy with progesterone or tamoxifen citrate. Epithelioid cells were most commonly found in proximity to medullary lesions and had a higher positive response to the anti-melanoma monoclonal antibody HMB-45 (an anti-glycoprotein derived from melanosomes), although they were not greatly influenced by the therapy. On the other hand, the small fusiform and oval cells showed a higher positive response to proliferating cell nuclear antigen (PCNA), matrix metalloproteinase (MMP)-2 and membrane type 1-matrix metalloproteinase (MT1-MMP). These findings were much more frequent in the pre-therapy samples, suggesting that the activation of MMP-2 by MT1-MMP is related to the hormonal activity and may play a major role in the destruction of pulmonary tissues. Other studies have also indicated an imbalance in elastic fiber degradation resulting from greater elastase (metalloproteinase) activity in the etiopathogenesis of pulmonary destruction.(32,33) The bronchiolar narrowing that results from smooth muscle cell proliferation causes air trapping and partially explains the (...truncated)