Micrograph of<unk> . H&E stain. CT scan of the lungs in a patient with<unk>  showing numerous thin walled cysts within the lungs.<unk>  can come to medical attention in several ways, most of which trigger a chest CT. Thin-walled cystic change in the lungs may be found incidentally on CT scans of the heart, chest or abdomen (on the cuts that include lung bases) obtained for other purposes. HRCTs of TSC patients reveals that about 20% of women have cystic change by age 20 and about 80% of women have cystic changes after age 40.<unk>  is sometimes revealed by chest CT in patients who present with an apparent primary spontaneous pneumothorax, but more often CT scanning is not ordered (in the United States) until recurrences occur. Progressive dyspnea on exertion without the exacerbations and remissions that are characteristic of asthma or COPD sometimes prompt a chest CT. A review of the CT by an expert familiar with<unk>  may increase diagnostic accuracy. Chylothorax can also bring<unk>  to attention. In some cases, a<unk>  diagnosis can be made with confidence on clinical grounds (without biopsy) in patients with typical cystic changes on high resolution CT scanning of the lung and findings of tuberous sclerosis, angiomyolipoma, lymphangioleiomyoma, chylothorax or serum VEGF-D > 800 pg/ml. If none of these clinical features are present, a biopsy may be necessary to make the diagnosis. Video-assisted thoracoscopic lung biopsy is the most definitive technique, but transbronchial biopsy has a yield of over 50% and can also be effective. The safety of the latter procedure in patients with diffuse cystic disease and the profusion of cystic change that predicts an informative biopsy are incompletely understood, however. Cytology of chylous fluids, aspirated abdominal nodes or lymphatic masses can also be diagnostic. Diagram 1 outlines a proposed algorithm for the diagnosis of<unk> .Diagram 1. Outlines a proposed algorithm for the diagnosis of<unk> . CT: computed tomography; TSC: tuberous sclerosis complex; AML: angiomyolipoma; VEGF-D: vascular endothelial growth factor D; TBBx: transbronchial biopsy; VATS: video-assisted thoracoscopic surgery. Chest radiograph The chest radiograph may appear relatively normal, even late in the disease, or may suggest hyperinflation only. As the disease progresses, the chest radiograph often demonstrates diffuse, bilateral and symmetric reticulonodular opacities, cysts, bullae or a "honeycomb" (i.e., pseudo fibrotic) appearance. Pleural effusion and pneumothorax may be apparent. Preservation of lung volumes in the presence of increased interstitial markings is a radiographic hallmark of<unk>  that helps distinguish it from most other interstitial lung diseases, in which alveolar septal and interstitial expansion tend to increase the lung's elastic recoil properties and decreased lung volumes. Computed tomography The high-resolution computed tomography (HRCT) chest scan is better than the chest radiograph to detect cystic parenchymal disease and is almost always abnormal at the time of diagnosis, even when the chest radiograph and pulmonary function assessments are normal. The typical CT shows diffuse round, bilateral, thin-walled cysts of varying sizes ranging from 1 to 45 mm in diameter. The numbers of cysts varies in<unk>  from a few to almost complete replacement of normal lung tissue. The profusion of cysts tends to be milder in patients with TSC-LAM than S-LAM, perhaps explained in part because TSC-LAM patients typically receive earlier screening. Pleural effusions are seen on CT in 12% of patients with S-LAM and 6% of patients with TSC-LAM. Other CT features include linear densities (29%), hilar or mediastinal lymphadenopathy (9%), pneumothorax, lymphangiomyoma, and thoracic duct dilation. Ground-glass opacities (12%) suggest the presence of interstitial edema due to lymphatic congestion. In patients with TSC, nodular densities on HRCT may represent multifocal micronodular pneumocyte hyperplasia (MMPH) made up of clusters of hyperplastic type II pneumocytes. MMPH may be present in males or females with TSC in the presence or absence of<unk> , but not in patients with S-LAM. MMPH is not typically associated with physiologic or prognostic consequences, but one case of respiratory failure due to MMPH has been reported. Ventilation-perfusion scans In one study ventilation-perfusion scans were abnormal in 34 of 35<unk>  patients. The most common abnormality was nonspecific diffuse heterogeneity, usually grossly matched. These authors also described an “unusual,” “speckling pattern” on the perfusion images in 74% of patients, consisting of “small, often peripheral collections of radioisotope.” Positron emission tomography<unk>  and AML lesions do not typically exhibit increased uptake of 18F-fluorodeoxyglucose on positron emission tomography (PET) scanning. Other neoplasms (or sources of inflammation) should therefore be considered in known or suspected<unk>  cases in which FDG-PET results are positive. Abdominal imaging Abnormalities on abdominal imaging, such as renal AML and enlarged lymphatic structures, are also common in<unk> . Fat density within a renal mass is pathognomonic of AMLs. AMLs are more prevalent and more frequently bilateral and large in patients with TSC-LAM than in patients with S-LAM. AML size correlates with the prevalence of pulmonary cysts in patients with TSC. One study CT imaged 256 patients with S-LAM and 67 with TSC-LAM. Renal AMLs were present in 32% of patients with S-LAM and 93% of patients with TSC-LAM. Hepatic AMLs were present in 2% of patients with S-LAM and 33% of patients with TSC-LAM. Ascites was uncommon, seen in fewer than 10% of patients with<unk> . Abdominal lymphangiomatosis, often containing both cystic and solid components, were seen in 29% of patients with S-LAM and 9% of patients with TSC-LAM. Central nervous system imaging Central nervous system abnormalities, such as cortical or subependymal tubers and astrocytomas, are common in patients with TSC, including those with TSC-LAM, but are not found in women with S-LAM. Moss and associates reported that women with S-LAM and TSC-LAM may have an increased incidence of meningioma, but the significance of that finding has been challenged. Pulmonary function studies Pulmonary function testing in patients with<unk>  may be normal or may reveal obstructive, restrictive or mixed patterns. Obstructive physiology is the most common abnormality. Quality-controlled lung function data were collected prospectively by the NHLBI Registry, a 5-year study of patients with<unk>  in centers around the United States. Spirometry revealed obstructive changes in about 57% of patients and normal results in 34%. Restriction, defined as a total lung capacity less than the lower limit of normal, was seen in 11%. Hyperinflation was present in about 6%. The average residual volume was 125% of predicted when measured by plethysmography, but was only 103% of predicted determined with gas dilution methods, suggesting significant air trapping in noncommunicating airspaces. Approximately 25% of patients with obstructive physiology may demonstrate bronchodilator responsiveness but may be less in more severe obstruction. The obstructive physiologic defect in<unk>  is primarily attributable to airflow obstruction. The earliest change in initial pulmonary function testing in various case series was abnormal gas transfer, as assessed by the diffusing capacity for carbon monoxide (DLCO), described in 82% to 97% of patients. It is not unusual for DLCO to be reduced out of proportion to forced expiratory volume in 1 second (FEV1). Reduction in DLCO and increase in residual volume are generally considered to be<unk> 's earliest physiologic manifestations. Cardiopulmonary exercise testing in a much larger cohort of patients with<unk>  revealed a reduced maximal oxygen consumption (VO2 max) and anaerobic threshold in 217 patients. Exercise-induced hypoxemia was found even in patients who did not have resting abnormalities in FEV1 and DLCO. In most patients, exercise was thought to be ventilation limited, owing to airflow obstruction and increased dead-space ventilation. Disease progression is usually accompanied by a progressive obstructive ventilatory defect. Decline in FEV1 is the most commonly used parameter to monitor disease progression. Although resting pulmonary hypertension appears to be unusual in<unk> , pulmonary arterial pressure often rises with low levels of exercise, related in part to hypoxemia. One study reported an increase in intraparenchymal shunts in dyspneic patients with<unk> , which may contribute to resting and exercise hypoxemia. Pathology Grossly,<unk>  lungs are enlarged and diffusely cystic, with dilated air spaces as large as several centimeters in diameter. Microscopic examination of the lung reveals foci of smooth muscle-like cell infiltration of the lung parenchyma, airways, lymphatics, and blood vessels associated with areas of thin-walled cystic change.<unk>  lesions often contain an abundance of lymphatic channels, forming an anastomosing meshwork of slit-like spaces lined by endothelial cells.<unk>  cells generally expand interstitial spaces without violating tissue planes but have been observed to invade the airways, the pulmonary artery, the diaphragm, aorta, and retroperitoneal fat, to destroy bronchial cartilage and arteriolar walls, and to occlude the lumen of pulmonary arterioles. There are two major cell morphologies in the<unk>  lesion: small spindle-shaped cells and cuboidal epithelioid cells.<unk>  cells stain positively for smooth muscle actin, vimentin, desmin, and, often, estrogen and progesterone receptors. The cuboidal cells within<unk>  lesions also react with a monoclonal antibody called HMB-45, developed against the premelanosomal protein gp100, an enzyme in the melanogenesis pathway. This immunohistochemical marker is very useful diagnostically, because other smooth muscle–predominant lesions in the lung do not react with the antibody. The spindle-shaped cells of the<unk>  lesion are
Lymphangioleiomyomatosis
Intravenous leiomyomatosis
Lymphangiomatosis
Angiodysplasia
Adenomyomatosis
Papillomatosis
Bagassosis
Fibromuscular dysplasia