Introduction
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.1,2,3,4,5
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.1 However, less than 5% of patients with TSC have pulmonary disease. When pulmonary features of LAM are identified in males, consider a diagnosis of TSC.2,6,7,8
Related eMedicine topics:
Lymphangioleiomyomatosis (Pulmonology)
Lymphoproliferative Syndrome, X-linked
Lymphoproliferative Disorders
Related Medscape topics:
Resource Center Pulmonary Arterial Hypertension
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Pathophysiology
In lymphangioleiomyomatosis (LAM), 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 tuberous sclerosis complex (TSC).2,3 The gene associated with TSC (TSC2) encodes a tumor-suppressor protein termed tuberin. 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
International
The prevalence of lymphangioleiomyomatosis (LAM) historically has been underestimated as a result of either delay in diagnosis or misdiagnosis. For example, the estimated prevalence of 1 case per million population in France, the United Kingdom, and the United States has been revised by a French group to 2.6 cases per million population. The increase in prevalence may be the result of a broader awareness of the disease among physicians and the establishment of international patient registries.
Mortality/Morbidity
Lymphangioleiomyomatosis (LAM) is a disease of progressive decline of pulmonary function resulting in respiratory failure, although the rate of deterioration is highly variable. Initial reports quoted survival periods of less than 10 years, but a retrospective study of the largest LAM patient series to date calculated 5-, 10-, and 15-year survival rates of 91%, 79%, and 71%, respectively. Patients can live more than 20 years after the initial diagnosis. If lung transplantation is performed in patients with end-stage LAM, survival is similar to that seen in patients receiving lung transplantation for other diseases (1- 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 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 racial predilection for lymphangioleiomyomatosis (LAM) is known.
Sex
Lymphangioleiomyomatosis (LAM) almost exclusively affects women. Disease exacerbation has been reported with pregnancy and the use of oral contraceptives.9
Age
The mean age of onset of lymphangioleiomyomatosis (LAM) is 33 years. Postmenopausal presentation is unusual and is more common in patients receiving exogenous estrogen.
Anatomy
The lungs in patients with lymphangioleiomyomatosis (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.
Presentation
An absence of family history, epilepsy, mental retardation, or cutaneous lesions can differentiate lymphangioleiomyomatosis (LAM) from tuberous sclerosis complex (TSC).
Initial symptoms usually are thoracic and (uncommonly) can precede abnormality on chest radiograph or pulmonary function tests (PFTs), 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. Although no evidence indicates a direct relationship between estrogen and LAM, the treatment of LAM has focused on reducing the production or effects of estrogen. No therapy has been found that is effective for all LAM patients.
The only known cure for patients with severe disease is lung transplantation.10 The mainstay of conservative management is hormonal therapy with progesterone, although the response is highly variable. Oxygen therapy may become necessary with worsening lung function. Treatment with cyclophosphamide, steroids, nitrogen mustard, and radiation has been reported to be unsuccessful. Tamoxifen alone or in combination with progesterone, oophorectomy, or gonadotropin-releasing hormone agonists has also been tried.
Management of pneumothorax is conventional, but recurrent episodes are managed with medical or surgical pleurodesis. Supportive management of chylous effusions includes 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 transplantation.
Preferred Examination
With clinical suspicion, lymphangioleiomyomatosis (LAM) has been diagnosed on the basis of compatible chest radiograph, pulmonary function tests (PFTs), and CT findings. CT is the most specific imaging test for diagnosing LAM. Compared to 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.11,12,13
Limitations of Techniques
Chest radiograph and pulmonary function test (PFT) findings, while suggestive of lymphangioleiomyomatosis (LAM), 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.
Differential Diagnoses
| Bronchiectasis | Idiopathic Pulmonary Fibrosis |
| Cystic Fibrosis, Thoracic | Neurofibromatosis Type 1 |
| Emphysema | Neurofibromatosis Type 2 |
| Eosinophilic Granuloma, Thoracic | Tuberous Sclerosis |
Other Problems to Be Considered
Recurrent Pneumocystis carinii pneumonia with cyst formation
More on Lymphangioleiomyomatosis |
 Overview: Lymphangioleiomyomatosis |
| Imaging: Lymphangioleiomyomatosis |
| Follow-up: Lymphangioleiomyomatosis |
| Multimedia: Lymphangioleiomyomatosis |
| References |
| Next Page » |
References
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Avila NA, Chen CC, Chu SC. Pulmonary lymphangioleiomyomatosis: correlation of ventilation-perfusion scintigraphy, chest radiography, and CT with pulmonary function tests. Radiology. Feb 2000;214(2):441-6. [Medline].
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Sundaram B, Gross BH, Oh E, Muller N, Myles JD, Kazerooni EA. Reader Accuracy and Confidence in Diagnosing Diffuse Lung Disease on High-Resolution Computed Tomography of the Lungs: Impact of Sampling Frequency. Acta Radiol. Jul 11 2008;1-6. [Medline].
Kumasaka T, Seyama K, Mitani K. Lymphangiogenesis in Lymphangioleiomyomatosis: Its Implication in the Progression of Lymphangioleiomyomatosis. Am J Surg Pathol. Aug 2004;28(8):1007-1016. [Medline].
Further Reading
Keywords
lymphangioleiomyomatosis, lymphangiomyomatosis, LAM, lymphangiomyoma, lymphoproliferative disorder, dyspnea, interstitial lung disease, lung disease, tuberous sclerosis complex, TSC, vascular obstruction, pulmonary obstruction, lung dysfunction, lung cyst, pulmonary cyst
