Chest
Volume 133, Issue 2, February 2008, Pages 507-516
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Recent Advances in Chest Medicine
Lymphangioleiomyomatosis: A Clinical Update

https://doi.org/10.1378/chest.07-0898Get rights and content

Lymphangioleiomyomatosis (LAM) is a rare, cystic lung disease that is associated with mutations in tuberous sclerosis genes, renal angiomyolipomas, lymphatic spread, and remarkable female gender restriction. The clinical course of LAM is characterized by progressive dyspnea on exertion, recurrent pneumothorax, and chylous fluid collections. Lung function declines at approximately twofold to threefold times the rate of healthy subjects, based on an annual drop in FEV1 of 75 to 120 mL in reported series. The diagnosis of pulmonary LAM can be made on high-resolution CT (HRCT) scan with reasonable certainty by expert radiologists, but generally requires a lung biopsy in cases in which tuberous sclerosis complex, angiomyolipomata, or chylous effusions are absent. The currently available treatment strategies are based on the antagonism of estrogen action, and are empiric and unproven. A trial of bronchodilators is warranted in patients with reversible airflow obstruction seen on pulmonary function testing. Pleurodesis should be performed with the initial pneumothorax, because the rate of recurrence is high. Angiomyolipomas that exceed 4 cm in size are more likely to bleed and should be evaluated for embolization. Air travel is well-tolerated by most patients with LAM. Lung transplantation is an important option for LAM patients, and can be safely performed by experienced surgeons despite prior unilateral or bilateral pleurodesis in most patients. Women with unexplained recurrent pneumothorax, tuberous sclerosis, or a diagnosis of primary spontaneous pneumothorax or emphysema in the setting of limited or absent tobacco use should undergo HRCT scan screening for LAM. Multicenter clinical trials based on several well-defined molecular targets are currently underway in the United States and Europe.

Section snippets

Molecular and Cellular Pathogenesis of LAM

LAM and TSC are caused by mutations in either of the tuberous sclerosis genes, TSC1 or TSC2, which control cell growth, survival, and motility through the Akt/mammalian target of rapamycin (mTOR) signaling pathway.121314 Deficiency or dysfunction of the encoded proteins, hamartin or tuberin, respectively, result in a loss of regulation of signals from upstream sources including cell surface tyrosine kinase and G protein-coupled receptors (Fig 1). The constitutive activation of the mTOR kinase

Prevalence, Diagnosis, Differential Diagnosis, and Pitfalls

Although global estimates of the prevalence of TSC (> 1 million affected) indicate that TSC-LAM is probably 5-fold to 10-fold more common than S-LAM, women with S-LAM represent approximately 85% of the > 240 patients enrolled in the National Heart, Lung, and Blood Institute (NHLBI) LAM Registry31 and the 1,300 patients registered with the LAM Foundation (Leslie Sullivan-Stacey, JD, CEO, The LAM Foundation; personal communication July 7, 2007). These observations suggest that TSC-LAM may be a

Natural History

The average age at the diagnosis of LAM in multiple series3150515253 is approximately 35 years. In a large cohort31 of 230 LAM patients reported by the NHLBI LAM Registry, 57% of patients exhibited an obstructive pattern and the average FEV1 was about 70% predicted. Interestingly, 34% of subjects had normal spirometry findings. The longitudinal lung function data from the registry is not yet available, but the NHLBI has reported that the mean (± SD) rate of decline in FEV1 and diffusing

Pleural Complications

Pneumothoraces ultimately occur in approximately 60 to 70% of patients with LAM, and the rate of recurrence is > 70%, the highest among all chronic lung diseases.6566 The average number of subsequent pneumothoraces for those who have had a sentinel pneumothorax is 4.4.31 The average lifetime pneumothorax-related burden for LAM patients with a history of pneumothorax who responded to a LAM Foundation questionnaire comprised approximately 3.5 events, 5 interventions, 1 month in the hospital, and

Renal Disease

About 93% of patients with TSC-LAM and 30 to 50% of patients with S-LAM have renal angiomyolipomas, which are benign renal tumors composed of dysplastic blood vessels, smooth muscle, and variable amounts of fat5970 (Fig 4). Interestingly, angiomyolipomas are the only known neoplastic lesions in which the intratumoral blood vessels are composed of the cells containing transforming mutations.71 In most patients, angiomyolipomas are clinically silent; however, flank pain, hydronephrosis,

Air Travel and Pregnancy

Many LAM patients have been advised to avoid air travel because of the theoretical risk of lung cyst rupture associated with atmospheric pressure changes during flight. In a questionnaire study of 276 patients who had taken 454 flights, Pollock-BarZiv et al73 found that air travel is generally well-tolerated by most patients with LAM. Symptoms of anxiety, chest pain, shortness of breath, cyanosis, or hemoptysis occurred during 10 to 20% of flights. Pneumothorax occurred during 10 flights,

Treatment

The current treatments for LAM are primarily based on the antagonism of estrogen action, and are empiric and unproven. The most commonly employed treatment is IM progesterone, which became the standard of care following a dramatic case report in 1987.74 Enthusiasm for the use of progestins has waned over time. In a retrospective analysis, Taveira-DaSilva et al75 found that progesterone treatment did not slow the decline in FEV1, and in fact, appeared to accelerate the rate of decline in Dlco

Current Clinical Trials

The Cincinnati Angiomyolipoma Sirolimus Trial was a proof-of-principle trial involving 20 patients with angiomyolipomas, including 11 with LAM. After 1 year receiving the drug AML, volume decreased by almost 50%, and airflow measurements of FEV1 and FVC increased by 5 to 10%.79 Although the improvements in angiomyolipoma volume and FEV1 waned somewhat after therapy with the drug was stopped, the initial response suggests that targeting the mTOR pathway has promise in the treatment of LAM. There

Lung Transplantation

The cumulative survival rate for LAM patients who have undergone transplantation in the United States is 65% at 5 years, which is equal to or better than the rate for other lung disease groups who underwent transplantation during the same period.82 Marked dyspnea, hypoxemia, and reduced Dlco on exertion develop in some patients with LAM in the absence of marked airflow obstruction; this subset of LAM patients may require transplantation evaluation before FEV1 reaches the typical threshold of

Screening and Follow-up

Evidence-based guidelines for the screening of women with pneumothorax or refractory dyspnea for LAM do not exist. The Tuberous Sclerosis Alliance recommends HRCT screening of all women with tuberous sclerosis at least once after age 18 years.85 The LAM Foundation Pleural Disease Consensus Committee recommends that HRCT scanning should be considered in all women with unexplained recurrent pneumothorax, tuberous sclerosis, or a diagnosis of primary spontaneous pneumothorax or emphysema in the

Future Directions

LAM and TSC research have identified a wealth of potential molecular targets and experimental therapies that may be appropriate for testing in clinical trials (Fig 5). These include mTOR inhibitors (eg, sirolimus and everolimus), Rheb inhibitors (eg, farnesyltransferase inhibitors and statins), selective estrogen antagonists (eg, fispemifene), tyrosine kinase inhibitors (eg, imatinib mesylate), metalloproteinase inhibitors (eg, doxycycline), angiogenesis inhibitors (eg, bevacizumab), and

ACKNOWLEDGMENT

The author would like to thank Drs. Cristopher Meyer, Matt Gillman, and Maurizio Luisetti for the images shown in Figure 2, Figure 3, Figure 4; and Sue Byrnes, Dr. Joel Moss, and the The LAM Foundation Pleural Consensus Committee for helpful discussion.

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    Dr. McCormack is the Scientific Director of the LAM Foundation, but receives no financial remuneration from that organization. He is the principal investigator of a LAM clinical trial, which is supported by The LAM Foundation, the Tuberous Sclerosis Alliance, the National Institutes of Health, and Wyeth Pharmaceuticals.

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