Background: Lymphangioleiomyomatosis (LAM) is a rare idiopathic disease affecting women that was first described by von Stossel in 1937. LAM is characterized by nonneoplastic peribronchial, perivascular, and perilymphatic proliferation of atypical smooth muscle resulting in vascular and airway obstruction, cyst formation, and a progressive decline in lung function. Typical radiographic findings of reticular interstitial lung disease, recurrent pneumothoraces, and recurrent chylous effusions have been described.

An association with renal angiomyolipomas is observed in as many as 50% of patients. The disease may occur sporadically or as part of the tuberous sclerosis complex (TSC) that includes mental retardation, seizures, and skin abnormalities. However, fewer than 5% of patients with TSC have pulmonary disease. When pulmonary features of LAM are identified in males, consider a diagnosis of TSC.

Pathophysiology: A proliferation of closely packed, spindle-shaped, smooth-muscle cells causes occlusion of the lymphatic system, resulting in chylous effusions or ascites. Similarly, obstruction of blood vessels can result in pulmonary hemorrhage, and obstruction of bronchioles can result in distal air trapping that causes cyst formation and the destruction of lung tissue. Rupture of subpleural cysts results in pneumothoraces. Others have proposed that the breakdown of lung tissue is caused by metalloproteinase enzymes present in cytoplasmic granules in the LAM smooth-muscle cells, which destroy interstitial collagen and elastin fibers. The proliferation of LAM cells typically is not associated with fibrosis.

Some LAM cells express estrogen and progesterone receptors, which may account for the role of hormones in disease predilection, progression, and treatment.

Etiology of the disease is unclear, but evidence suggests a link to TSC. The gene associated with TSC (TSC2) encodes a tumor-suppressor protein termed tuberin. Recently, a mutation that results in loss of heterozygosity of this gene (and possibly deficient tuberin activity) was discovered in LAM smooth-muscle cells, in the lymph nodes of a patient with retroperitoneal LAM, and in LAM-associated angiomyolipomas. Note that other cell lines in the same patients did not possess this mutation; therefore, patients with LAM may have a mosaic genotype, unlike patients with TSC.

Frequency:

• In the US: The prevalence of LAM historically has been underestimated as a result of either delay in diagnosis or misdiagnosis. For example, the estimated incidence of 1 per 1,000,000 in France, the United Kingdom, and the US has been revised by a French group to 2.6 per 1,000,000. The increase in incidence may be the result of a broader awareness of the disease among physicians and the establishment of international patient registries.

• Internationally: Please refer to Frequency in the US for a discussion on international incidence.

Mortality/Morbidity: LAM is a disease of progressive decline of pulmonary function resulting in respiratory failure, although the rate of deterioration varies. Initial reports quoted survival periods of fewer than 10 years, but a recent retrospective study of the largest LAM patient series to date calculated 5-year, 10-year, and 15-year survival rates of 91%, 79%, and 71%, respectively. If a lung transplant is performed in patients with end-stage LAM, survival is similar to lung transplants for other diseases (1-y and 3-y survival rates of 70% and 50%, respectively).

Common presenting symptoms include dyspnea, cough, and chest pain. In the course of one series, over an 18-month period in patients with known LAM, the prevalence of pneumothorax and chylothorax was 68% and 29%, respectively. Recurrent pneumothoraces and chylous effusion were present in 29% and 9% of these patients, respectively. Approximately 50% of patients have renal angiomyolipomas, which commonly are present at the time of diagnosis, although small and asymptomatic. Multiple angiomyolipomas or tumors larger than 4.0 cm occasionally may cause shock or death as a result of massive hemorrhage.

Chyloptysis, hemoptysis, wheezing, chest pain, chylous ascites, lymphangiomyoma masses, chylous vaginal discharge, chyluria, uterine fibroids, and lower-extremity lymphedema have been reported.

Race: No known racial predilection exists.

Sex: LAM almost exclusively affects women. Disease exacerbation has been reported with pregnancy and the use of oral contraceptives.

Age: The mean age of onset is 33 years. Postmenopausal presentation is unusual and is more common in patients receiving exogenous estrogen.

Anatomy: The lungs in patients with LAM contain multiple air-filled cysts distributed uniformly and bilaterally and ranging from 2-50 mm, with most from 5-15 mm. Cysts are surrounded by relatively normal lung tissue. While most cysts are round, they can be polygonal or bizarre. The number and size of cysts increase as the disease progresses.

Clinical Details: An absence of family history, epilepsy, mental retardation, or cutaneous lesions can differentiate LAM from TSC.

Initial symptoms usually are thoracic and (uncommonly) can precede abnormality on chest radiograph or pulmonary function tests (PFT), resulting in misdiagnosis. Crackles, pleural effusion, ascites, or cor pulmonale may be detected on physical examination. PFT findings vary. A reduction in the diffusion capacity of carbon monoxide is the most common initial abnormality. Obstructive physiology is more common than restrictive, but findings may be mixed. A trend toward hyperinflation and increased total lung capacity is seen. The ratio of forced expiratory volume in 1 second to forced vital capacity (FEV₁/FVC) can be used to monitor disease progression.

Pregnancy, estrogen replacement therapy, prolonged air travel, or trips to high-altitude locales are not advised for LAM patients.

Currently, the only known cure for the disease is lung transplant. The mainstay of conservative management is hormonal therapy with progesterone, although the response is highly variable. Tamoxifen alone or in combination with progesterone, oophorectomy, and gonadotropin-releasing hormone agonists also are being used. Treatment withcyclophosphamide, steroids, nitrogen mustard, and radiation have been reported to be unsuccessful.

Management of pneumothorax is conventional, but recurrent episodes are managed with medical or surgical pleurodesis. Supportive management of chylous effusions include nutritional modifications to low-fat diets containing medium-chain triglycerides. In patients with end-stage disease, oxygen inhalation is the final therapy prior to lung transplant.

Preferred Examination: With clinical suspicion, LAM has been diagnosed on the basis of compatible chest radiograph, PFT, and CT findings. CT is the most specific imaging test; however, the criterion standard is open-lung biopsy. Transbronchial biopsy followed by immunohistochemical staining of sampled tissue with homatropine methylbromide 45 (HMB45) is less invasive. HMB45, a monoclonal antibody that binds to proteins produced by melanoma cell lines, is both sensitive and specific for making the diagnosis of LAM.

Limitations of Techniques: Chest radiograph and PFT findings, while suggestive, can be nonspecific and may be normal despite the presence of symptoms. Plain radiography may not detect the thin-walled cysts identified on CT and may underestimate the extent of the disease. PFT results vary depending on the extent of disease. CT, and especially high-resolution scanning, may reveal distinct findings that obviate the need for biopsy; however, diseases such as emphysema occasionally must be excluded. CT detection of a renal angiomyolipoma or chylous ascites further supports the diagnosis.

Transbronchial biopsy without staining with HBM45 usually does not provide enough lung tissue for diagnosis. Open-lung biopsy may make lung transplant more difficult technically.

DIFFERENTIALS

Bronchiectasis
Cystic Fibrosis, Thoracic
Emphysema
Eosinophilic Granuloma, Thoracic
Idiopathic Pulmonary Fibrosis
[Neurofibromatosis Type I]
[Neurofibromatosis Type II]
Tuberous Sclerosis

Other Problems to be Considered:

Recurrent Pneumocystic carinii pneumonia with cyst formation

X-RAY

Findings: Initial film is abnormal in more than 95% of patients.

A symmetric, diffuse, reticular interstitial pattern, caused by summation of multiple cyst walls, is typical. If Kerley B lines are present, they may be the result of interstitial edema related to lymphatic obstruction. Multiple cysts become visible as they enlarge. Occasionally, patients may present with pneumothorax or chylous pleural effusion.

LAM is one of the few 'interstitial' diseases in which lung volumes are maintained or increased. Cystic fibrosis and Langerhans cell histiocytosis (eosinophilic granuloma) share this feature.

False Positives/Negatives: Large lung volumes and interstitial disease on plain film also can be seen with Langerhans cell histiocytosis, sarcoidosis, and extrinsic allergic alveolitis. Occasionally, emphysema presents with a similar pattern as a result of summation of widespread small bullae.