Brazilian Thoracic Association recommendations for the management of lymphangioleiomyomatosis

Abstract

Lymphangioleiomyomatosis (LAM) is a rare disease, characterized as a low-grade neoplasm with metastatic potential that mainly affects women of reproductive age, in which there is proliferation of atypical smooth muscle cells (LAM cells) and formation of diffuse pulmonary cysts. It can occur in a sporadic form or in combination with tuberous sclerosis complex. In recent decades, a number of advances have been made in the understanding of the pathophysiology and management of LAM, leading to improvements in its prognosis: identification of the main genetic aspects and the role of the mechanistic target of rapamycin (mTOR) pathway; relationship with hormonal factors, mainly estrogen; characterization of pulmonary and extrapulmonary manifestations in imaging studies; identification and importance in the diagnosis of VEGF-D; a systematic diagnostic approach, often without the need for lung biopsy; use of and indications for the use of mTOR inhibitors, mainly sirolimus, for pulmonary and extrapulmonary manifestations; pulmonary rehabilitation and the management of complications such as pneumothorax and chylothorax; and the role of and indications for lung transplantation. To date, no Brazilian recommendations for a comprehensive approach to the disease have been published. This document is the result of a non-systematic review of the literature, carried out by 12 pulmonologists, a radiologist, and a pathologist, which aims to provide an update of the most important topics related to LAM, mainly to its diagnosis, treatment, and follow-up, including practical and multidisciplinary aspects of its management.

Figure 1. Pulmonary and extrapulmonary findings associated with lymphangioleiomyomatosis (LAM). A) Minimum-intensity projection reconstruction of a coronal CT scan, showing multiple scattered lung cysts of varying sizes, together with a small pneumothorax on the right (arrow). B) Axial CT scan of the chest, with lung window settings, showing diffuse cysts typical of LAM, together with a ground-glass opacity in the lower right lobe, presumably due to lymphatic congestion/filling or alveolar hemorrhage. C) Axial CT scan of the chest, with lung window settings, showing moderate pleural effusion, proven to be chylous in the laboratory analysis. D) Unenhanced axial CT scan of the abdomen, showing multiple nodular lesions with adipose attenuation in the renal parenchyma, characteristic of angiomyolipomas. E) Axial CT scan of the abdomen showing multiple retroperitoneal hypoattenuating nodular lesions, characteristic of lymphangioleiomyomas.

Figure 2. Differential diagnosis of lymphangioleiomyomatosis. Minimum-intensity projection reconstructions of coronal CT scans in A, C, E and G, and axial CT scans, with lung window settings, in B, D, F and H. In A and B, pulmonary Langerhans cell histiocytosis, with cysts of variable sizes/shapes and some small centrilobular nodules, predominantly in the upper lung fields. Note that the costophrenic recesses are preserved. In C and D, lymphocytic interstitial pneumonia, with some of the cysts having an axial distribution, mainly peribronchovascular, concentrated in the lung bases. In E and F, Birt-Hogg-Dubé syndrome, in which the cysts are typically larger and elliptical, usually with a paramediastinal distribution in the lower lung fields. In G and H, an unusual manifestation of constrictive bronchiolitis, with sparse, randomly distributed cysts.

Figure 3. Other lesions associated with tuberous sclerosis complex. A) Axial CT scan of the chest, showing scattered pulmonary cysts related to lymphangioleiomyomatosis and some ground-glass micronodules, presumably associated with micronodular and multifocal hyperplasia of type II pneumocytes (arrowheads). B) Axial CT scan of the dorsal spine, showing multiple sclerotic foci concentrated in the posterior vertebral elements (arrows). C) Axial CT scan of the chest, with mediastinal window settings, showing foci of myocardial fat accumulation (arrowheads). D) Axial MRI of the skull, with fluid-attenuated inversion recovery weighting, showing cortical tubers (arrowheads).

Figure 4. Evolution of the cystic pulmonary manifestation of lymphangioleiomyomatosis. Coronal CT scans of the chest, with minimum-intensity projection reconstruction, obtained at baseline (A) and at five years after diagnosis (B), showing progression of the condition, with increases in the number and size of the cysts.

Figure 5. Photomicrographs demonstrating histopathological and immunohistochemical aspects in a patient with lymphangioleiomyomatosis (LAM). A) Proliferation of LAM cells with formation of small nodules throughout a pulmonary cystic lesion (H&E). B) Immunohistochemistry showing LAM cells that stained positive for smooth muscle actin (B); HMB-45 (C); and beta-catenin (D, membrane and cytoplasmic patterns).

Figure 6. Algorithm for the diagnostic approach to lymphangioleiomyomatosis (LAM ).