Review articleLymphangioleiomyomatosis: A review
Introduction
Lymphangioleiomyomatosis (LAM) is a rare disease of unknown etiology described classically as occurring in women of reproductive age, and occasionally in postmenopausal women [1], [2], [3], [4]. The disease often arises spontaneously in patients with no evidence of genetic disease and is present in approximately one third of women with tuberous sclerosis complex [5], [6]. The pathology of LAM is represented by the proliferation of immature smooth muscle cells in the walls of airways, venules and lymphatic vessels in the lung [7], [8]. Proliferation of these cells results in narrowing of the airways, obstruction, and air trapping. Damaged alveoli combine, and in time lead to the development of cystic lung lesions and fluid-filled cysts in the lymphatics (lymphangioleiomyomas) [9]. The disease follows an insidious course and the rate of progression is variable ranging from a few years to over three decades before culminating in respiratory failure [10].
The estimated incidence of LAM is between 1–2.6 cases per 1,000,000 women [9], [11]. The true incidence is likely under-reported because LAM is often mistakenly diagnosed for asthma, chronic obstructive lung disease, or bronchitis. The two most common presenting symptoms of LAM are dyspnea on exertion and pneumothorax [1]. Pneumothoraces are often recurrent, even in patients with normal chest X-rays (CXR) [2] and have been reported to occur at a frequency of 40 to 80% in patients with LAM [7]. Other less common presenting symptoms include hemoptysis, non-productive cough, chylous pleural effusion and chylous ascites [1]. While these symptoms are less likely present initially, they often develop with disease progression [1], [2].
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Physical findings
The most common complications of LAM — pneumothorax, chylous pleural effusion, and hemoptysis can be explained at least in part by the proliferation of atypical smooth muscle cells around the bronchioles, lymphatics and venules, respectively [3]. The bronchioles may be circumferentially narrowed by the peribronchiolar proliferating tissue [9]. Airway obstruction and air trapping contribute to the formation of parenchymal cysts and pneumothorax. Focal or diffuse thickening of the walls of air
Pathogenesis and tuberous sclerosis complex (TSC) association
LAM and the Tuberous Sclerosis Complex may share a common genetic relationship. TSC is caused by germline mutations of either the TSC1 or TSC2 gene located on chromosomes 9q34 and 16p13, respectively. Both of these genes are tumor suppressor genes encoding hamartin (TSC1) and tuberin (TSC2) [23].Tumor in either condition is associated with a loss of heterozygosity (LOH) at one of the two genes [14], [45]. The tumor suppressor gene TSC2 has been implicated in the etiology of LAM, as mutations
Radiography
The chest radiographic findings may be normal or may show diffuse reticular or miliary changes throughout all lung zones with overexpansion of the lungs. Ground glass opacities may be noted corresponding to pulmonary hemosiderosis and/or relatively diffuse proliferation of immature smooth muscle cells [2]. A pattern of reticulation results from the coalescence of numerous pulmonary cysts [18]. An alternative cause of this pattern on CXR is Langerhans' Cell Histiocytosis (LCH), from which LAM
Hormone association
LAM classically occurs in women of childbearing age and its presentation in postmenopausal women is generally considered unusual. It is likely that estrogen plays a fundamental role in disease progression. The disease is never seen before menarche, known to accelerate during pregnancy and observed to subside after oophorectomy. In addition, receptors of estrogen and progesterone have been located in a subpopulation of the atypical smooth muscle cells that are characteristic of the disease [29],
Diagnosis of LAM
Any young woman who presents with emphysema, recurrent pneumothorax, or a chylous pleural effusion should raise suspicion for LAM. High resolution CT scan can often confirm the diagnosis, and tissue confirmation may not always be necessary [19]. However, lung tissue is often obtained through either thoracoscopic or open lung biopsy. Transbronchial lung biopsy can provide adequate tissue sample for pathologic evaluation. LAM can be readily diagnosed by its characteristic histological findings.
Pulmonary function testing
The lungs of patients suffering from LAM are often hyper inflated. Typically patients demonstrate an increased total lung capacity (TLC). Pulmonary function tests frequently reveal an “obstructive” or “mixed” pattern [1], [2], [20]. An increase in residual volume (RV) and RV/TLC ratio as a result of the air trapping is generally present. Patients will demonstrate limitations to airflow and pulmonary function tests often show reduced flow rates (FEV1). Twenty per cent of patients have positive
LAM in men
Of the four reported cases of LAM occurring in males, the report that indicates the occurrence of LAM in a chromosomally normal man unaffected by TSC is of particular interest [42]. Schiavina et al. reported the case of a phenotypically and karyotypically (TSC1 and TSC2 germ line mutations were not detected at DNA analysis) normal man with left pneumothorax and massive pulmonary collapse with widespread thin-walled cysts throughout both lungs. Interestingly, the HMB-45-positive cells lining the
Treatment
Although Taylor et al. found no therapeutic benefit from oophorectomy or anti-estrogen therapy with tamoxifen, progesterone was reported beneficial in at least some patients leading to their recommendation of its use in all symptomatic patients [1]. However, these findings have not been demonstrated consistently and a recent retrospective analysis performed by Taviera-DaSilva et al. reported that progesterone therapy did not slow decline in lung function and may have limited use in the
Emerging clinical picture
Recent work by Cohen et al. has revisited the clinical presentation via the utilization of multiple large registries including international groups of LAM patients [37]. Their comprehensive survey suggests that older women (50% without pneumothorax) are now being diagnosed with LAM. The mean age of diagnosis appears to be increasing over time. With the identification of more patients and the utilization of data registry the typical presentation is becoming equally a disease of women 45–60 years
Conclusion
Lymphangioleiomyomatosis is the result of disorderly smooth muscle proliferation throughout the bronchioles, alveolar septa, perivascular spaces, and lymphatics, resulting in the obstruction of small airways leading to pulmonary cyst formation and pneumothorax. Lymphatic obstruction leads to chylous pleural effusion, leading to pulmonary cyst formation pneumothoraces. LAM occurs in a sporadic form which predominantly affects females often in the childbearing age. A patient who presents with
Learning points
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Pulmonary lymphangioleiomyomatosis (LAM) is a rare lung disease that afflicts young women of childbearing age
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Chest CT often demonstrates multiple well-defined thin-walled cysts, homogenously distributed and present throughout all lung zones with relative apical sparing
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Thin-section CT has a higher diagnostic yield than plain radiography and may demonstrate parenchymal cysts even in the presence of a normal CXR
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Estrogen administration and pregnancy may accelerate disease progression given that
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These authors have contributed equally to the production of this Review Article.