2% of patients with s-lam and 33% of patients with tsc-lam. ascites was uncommon, seen in fewer than 10% of patients with lam. 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 lam 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 five-year study of patients with lam 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 lam 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 lam's earliest physiologic manifestations. cardiopulmonary exercise testing in a much larger cohort of patients with lam 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 lam, 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 lam, which may contribute to resting and exercise hypoxemia. pathology grossly, lam 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. lam lesions often contain an abundance of lymphatic channels, forming an anastomosing meshwork of slit-like spaces lined by endothelial cells. lam 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 lam lesion: small spindle-shaped cells and cuboidal epithelioid cells. lam cells stain positively for smooth muscle actin, vimentin, desmin, and, often, estrogen and progesterone receptors. the cuboidal cells within lam 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 lam lesion are more frequently proliferating cell nuclear antigen positive than the cuboidal cells, consistent with a proliferative phenotype. compared with cigar-shaped normal smooth muscle cells, spindle-shaped lam cells contain less abundant cytoplasm and are less eosinophilic. estrogen and progesterone receptors are also present in lam lesions, but not in adjacent normal lung tissue. lam lesions express lymphatic markers lyve-1, prox1, podoplanin and vegfr-3. the smooth muscle-like cells of amls are morphologically and immunohistochemically similar to lam cells, including reactivity with antibodies directed against actin, desmin, vimentin, and hmb-45 as well as estrogen and progesterone receptors. unlike the dilated airspaces in emphysema, the cystic spaces found in lam may be partially lined with hyperplastic type ii cells. treatment an fda-approved drug for treatment of lam, the mtor inhibitor sirolimus, is available for stabilization of lung function decline. lung transplant remains the last resort for patients with advanced disease. pneumothorax pneumothoraces in lam patients tend to recur, especially after conservative management such as observation, aspiration or simple tube thoracostomy. over 65% of lam patients develop pneumothorax during the course of their illness, averaging 3.5 pneumothoraces in those who have at least one pneumothorax. the lam foundation pleural consensus group advocated the use of a pleural symphysis procedure with the first pneumothorax, given the greater than 70% chance of recurrence. chemical sclerosis, mechanical abrasion, talc poudrage and pleurectomy have been effective in patients with lam, but mechanical abrasion is preferred for those who may require pulmonary transplantation in the future. about half of lam patients who have undergone transplant have had a prior pleurodesis procedure, and more than 75% of those had had prior bilateral pleurodesis. although pleurodesis is not a contraindication to transplantation, it can result in increased perioperative bleeding. chylothorax chyle does not generally cause pleural inflammation or fibrosis. small stable chylous effusions rarely require intervention once the lam diagnosis is made. shortness of breath may mandate possibly repeated drainage. sirolimus is effective for chylous effusions and most experts believe it should be used as the first line of therapy. imaging the source of the leak with heavy t2-weighted mri or contrast lymphangiography is an advised for refractory effusions. some leaks are amenable to embolization through catheters threaded from groin lymph nodes into the thoracic duct. thoracic duct ligation can be considered, but since thoracic effusions sometimes originate from ascites that are siphoned into the chest by the bellows action of the thorax, it is important to rule out an abdominal source before considering this option. pleural symphysis may be required to prevent nutritional and lymphocyte deficiencies that can result from repeated taps or persistent drainage. chemical pleurodesis is generally an effective therapy for chylothorax, as is mechanical abrasion and talc poudrage. angiomyolipoma renal angiomyolipomas (amls) may require embolization or cauterization for control of bleeding, a complication that is thought to be more common when tumor diameter exceeds 4 cm. the extent of aneurysmal change may determine bleeding risk. serial abdominal imaging should be performed to assess aml size at 6- to 12-month intervals, at least until trends in growth are clear. nephron sparing partial resections may be considered for very large tumors. nephrectomy is sometimes required for tumors with intravascular extension or other reasons, but is rarely the approach of choice for amls that can be managed by less invasive means. everolimus is approved by the us food and drug administration (fda) for aml treatment. lymphangioleiomyoma lymphangioleiomyomatoses are fluid-filled hypodense structures present in the retroperitoneal regions of the abdomen and pelvis in about 30% of lam patients. they generally do not require intervention. biopsy or resection can lead to prolonged leakage. mtor inhibitors are effective at shrinking the size of lymphangioleiomyomatosis, and can lead to total resolution. management-other estrogen-containing medications can exacerbate lam and are contraindicated. agents that antagonize the effects of estrogen have not been proven to be effective for treatment, but no proper trials have been done. a trial of bronchodilators should be considered in lam patients, because up to 17–25% have bronchodilator-responsive airflow obstruction. oxygen should be administered to maintain oxyhemoglobin saturations of greater than 90% with rest, exercise and sleep. bone densitometry should be considered in all patients who are immobilized and/or on antiestrogen therapies, and appropriate therapy instituted for osteoporotic patients. proper attention should be paid to cardiovascular health following natural or induced menopause. immunizations for pneumococcus and influenza should be kept up to date. pulmonary rehabilitation seems to be particularly rewarding in young, motivated patients with obstructive lung disease, but studies to assess this intervention's effect on exercise tolerance, conditioning and quality of life have not been done. medication sirolimus is an mtor inhibitor that stabilizes lung function and improves some measures of life in lam patients. it is approved by the fda for use in lam, based on the results of the multicenter international lam efficacy and safety of sirolimus (miles) trial. miles data supports the use of sirolimus in patients who have abnormal lung function (i.e. fev1<70% predicted). whether the benefits of treatment outweigh the risks for asymptomatic lam patients with normal lung function is not clear, but some physicians consider treatment for declining patients who are approaching the abnormal range for fev1. sirolimus also appears to be effective for the treatment chylous effusions and lymphangioleiomyomatosis. the benefits of sirolimus only persist while treatment continues. the safety of long term therapy has not been studied. potential side effects from mtor inhibitors include swelling in the ankles, acne, oral ulcers, dyspepsia, diarrhea, elevation of cholesterol and triglycerides, hypertension and headache. sirolimus pneumonitis and latent malignancy are more serious concerns, but occur infrequently. sirolimus inhibits wound healing. it is important to stop therapy with the drug for 1–2 weeks before and after elective procedures that require optimal wound healing. precautions must be taken to avoid prolonged sun exposure due to increased skin cancer risk. treatment with another mtor inhibitor, everolimus, was reported in a small, open-label trial to be associated with improvement in fev1 and six-minute walking distance. serum levels of vegf-d and collagen iv were reduced by treatment. adverse events were generally consistent with those known to be associated with mtor inhibitors, although some were serious and included peripheral edema, pneumonia, cardiac failure and pneumocystis jirovecii infection. escalating doses of everolimus were used, up to 10 mg per day; higher than what is typically used clinically for lam. serum vegf-d concentration is useful, predictive and prognostic biomarker. higher baseline vegf-d levels predicts more rapid disease progression and a more robust treatment response. hormonal approaches to treatment have never been tested in proper trials. in the absence of proven benefit, therapy with progesterone, gnrh agonists (e.g., leuprorelin, goserelin) and tamoxifen are not routinely recommended. doxycycline had no effect on the rate of lung function decline in a double blind trial. sirolimus is often effective as first-line management for chylothorax. if chylous leakage or accumulations persist despite treatment, imaging with heavy t2 weighted mri, mri lymphangiography or thoracic duct lymphangiography can be considered. pleural fusion procedures can be considered in refractory cases. prognosis survival estimates vary, dependent on mode of presentation or ascertainment, and have generally trended upward, probably due to earlier recognition through more widespread use of ct scanning. in a recent population-based cohort survey, median survival was found to be 29 years. data from earlier, large case series indicated that 38% to 78% of patients were alive at 8.5 years from the time of disease onset. patients typically develop progressive airflow obstruction. in a cohort of patients in the united kingdom, 10 years after symptom onset, 55% of 77 patients were breathless walking on flat ground and 10% were housebound. the average annual rate of decline in fev1 and dlco in 275 patients studied in a single pulmonary function laboratory at the nhlbi was 75 ± 9 ml, and 0.69 ± 0.07 ml/min/mm hg, respectively. in other series from europe, the rate of decline in fev1 was considerably higher, estimated at approximately 100 to 120 ml/yr. in the miles trial, patients in the placebo group lost 134 cc/yr. there was some evidence in these studies that rate of decline in lung function correlates with initial dlco, with menopausal status and high baseline vegf-d. estimates of median survival vary from 10 to 30 years, depending on whether hospital-based or population-based cohorts are studied. epidemiology lam is almost completely restricted to women. while lung cysts consistent with lam are