Review article
Lymphangioleiomyomatosis: A review

https://doi.org/10.1016/j.ejim.2007.10.015Get rights and content

Abstract

Lymphangioleiomyomatosis (LAM) is a rare disease, of unknown etiology, affecting women almost exclusively. Microscopically, LAM consists of a diffuse proliferation of smooth muscle cells. LAM can occur without evidence of other disease (sporadic LAM) or in conjunction with tuberous sclerosis complex (TSC). TSC is an autosomal dominant tumor suppressor gene syndrome characterized by seizures, mental retardation, and tumors in the brain, heart, skin, and kidney. LAM commonly presents with progressive breathlessness or with recurrent pneumothorax, chylothorax, or sudden abdominal hemorrhage. Computed tomography (CT) scans show numerous thin-walled cysts throughout the lungs, abdominal angiomyolipomas, and lymphangioleiomyomas. No effective treatment currently exists for this progressive disorder. The prevalence of lymphangioleiomyomatosis is probably underestimated based on its clinical latency and the absence of specific laboratory tests. With the utilization of international LAM data registries the “classical” picture of the disorder appears to be evolving as a larger number of patients are evaluated. An increased awareness of LAM and its common clinical presentation may advance the development of new therapeutic strategies and reduce the number of mistakenly diagnosed patients.

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].

Section snippets

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

  • Pulmonary lymphangioleiomyomatosis (LAM) is a rare lung disease that afflicts young women of childbearing age

  • Chest CT often demonstrates multiple well-defined thin-walled cysts, homogenously distributed and present throughout all lung zones with relative apical sparing

  • Thin-section CT has a higher diagnostic yield than plain radiography and may demonstrate parenchymal cysts even in the presence of a normal CXR

  • Estrogen administration and pregnancy may accelerate disease progression given that

References (50)

  • T.A. Smolarek et al.

    Evidence that lymphangiomyomatosis is caused by TSC2 mutations: chromosome 16p13 loss of heterozygosity in angiomyolipomas and lymph nodes from women with lymphangiomyomatosis

    Am J Hum Genet

    (1998)
  • K.T. Patton et al.

    Benign metastasizing leiomyoma: clonality, telomere length and clinicopathologic analysis

    Mod Pathol

    (Jan 2006)
  • M.G. Fiore et al.

    Abdominal lymphangioleiomyomatosis in a man with Klinefelter syndrome: the first reported case

    Ann Diagn Pathol

    (Apr 2005)
  • F. McCormack et al.

    Pulmonary cysts consistent with lymphangioleiomyomatosis are common in women with tuberous sclerosis

    Chest

    (2002)
  • J.R. Taylor et al.

    Lymphangioleiomyomatosis: clinical course in 32 patients

    N Engl J Med

    (1990)
  • M. Kitaichi et al.

    Pulmonary Lymphangioleiomyomatosis: a report of 46 patients including a clinicopathologic study of prognostic factors

    Am J Respir Crit Care Med

    (1995)
  • B. Corrin et al.

    Pulmonary lymphangioleiomyomatosis: a review

    Am J Pathol

    (1975)
  • K.G. Kalassian et al.

    Lymphangioleiomyomatosis: new insights

    Am J Respir Crit Care Med

    (1997)
  • D.N. Franz et al.

    Mutation and radiographic analysis of pulmonary disease consistent with lymphangioleiomyomatosis and micronodular pneumocyte hyperplasia in women with tuberous sclerosis

    Am J Respir Crit Care Med

    (2001)
  • C.B. Carrington et al.

    Lymphangioleiomyomatosis: physiologic-pathologic-radiologic correlations

    Am Rev Respir Dis

    (1977)
  • A. Taviera-DaSilva et al.

    Lymphangioleiomyomatosis

    Cancer Control

    (2006)
  • S. Johnson

    Lymphangioleiomyomatosis: clinical features, management and basic mechanisms

    Thorax

    (1999)
  • A. Yamazaki et al.

    An early case of pulmonary lymphangioleiomyomatosis diagnosed by video-assisted thoracoscopic surgery

    Ann Thorac Cardiovasc Surg

    (2005)
  • F. Bonetti et al.

    Transbronchial biopsy in lymphangioleiomyomatosis of the lung: HMB 45 for diagnosis

    Am J Surg Pathol

    (1993)
  • A. Boehler et al.

    Lung transplantation for lymphangioleiomyomatosis

    N Engl J Med

    (1996)
  • Cited by (0)

    1

    These authors have contributed equally to the production of this Review Article.

    View full text