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Lymphangioleiomyomatosis 

Lymphangioleiomyomatosis
Chapter:
Lymphangioleiomyomatosis
Author(s):

S.J. Bourke

and D.J. Hendrick

DOI:
10.1093/med/9780199204854.003.181406_update_003

July 30, 2015: This chapter has been re-evaluated and remains up-to-date. No changes have been necessary.

Update:

Notes on treatment with sirolimus (rapamycin).

Updated on 29 May 2014. The previous version of this content can be found here.
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Essentials

Lymphangioleiomyomatosis is caused by mutations (usually sporadic, sometimes in tuberous sclerosis) of the TSC1 or TSC2 genes and results in cystic destruction of the lungs, with CT features being sufficiently characteristic to establish the diagnosis in many cases. Two-thirds of patients suffer pneumothoraces. Hormonal therapy with progesterone or tamoxifen is usually given for progressive disease; medical or surgical pleurodesis is advisable; lung transplantation is the main option for advanced disease.

Lymphangioleiomyomatosis (LAM) is a rare disease in which lymphatics (‘lymph’), blood vessels (‘angio’), and airways are infiltrated by proliferating smooth muscle cells (‘leiomyo’), resulting in cystic destruction of the lungs, pneumothoraces, chylous effusions, and haemorrhage. It can occur as a sporadic disorder or in association with tuberous sclerosis. Both sporadic and tuberous sclerosis-associated LAM result from mutations of the tumour suppressor genes TSC1 (encoding hamartin) and TSC2 (encoding tuberin). Hamartin and tuberin form a cytoplasmic complex and so inhibit the protein mTOR which stimulates cell proliferation. Sporadic LAM occurs exclusively in women, predominantly between the menarche and the menopause. Exceptionally rare cases of LAM have been reported in men with tuberous sclerosis, but the disease is almost confined to women. This suggests that the proliferation of LAM cells depends on female sex hormones, and oestrogen and progesterone receptors have been found in some LAM cells.

Sporadic LAM is due to somatic (noninherited) mutations in the TSC1 and TSC2 genes and occurs in about 2 in a million women. Tuberous sclerosis results from a germ-line mutation of the TSC1 and TSC2 genes and is an autosomal dominant inherited disorder (OMIM 191 100) whose manifestations include epilepsy, learning difficulties, skin lesions (angiofibromas, shagreen patches), and hamartomas in the brain, kidneys, and other organs (see Chapters 24.17 and 24.17.1). Most women with tuberous sclerosis ultimately develop evidence of LAM on CT as they get older, with 63% developing symptoms and 12.5% dying of LAM.

Pneumothorax occurs in about two-thirds of patients with LAM and is a common mode of presentation. Other manifestations include breathlessness from progressive parenchymal involvement, cough, haemoptysis, and chest pain. Involvement of the thoracic duct may result in chylous pleural effusions and ascites. Other abdominal features include renal angiomyolipomas, cystic lymphatic masses, and lymphadenopathy. Renal angiomyolipomas are present in about 50% of patients: they rarely cause symptoms, but bleeding may require treatment by embolization or surgical resection.

The chest radiograph typically shows diffuse small cysts with reticulonodular shadowing, but normal or increased lung volumes. Lung function tests usually show progressive airways obstruction and reduced gas transfer. The CT features are sufficiently characteristic to establish the diagnosis in many cases, with well-defined cystic airspaces with thin walls distributed throughout both lungs (Fig. 18.14.6.1), and more widespread use of CT imaging is detecting milder cases in an extended spectrum of patients including some postmenopausal women. Lung biopsy may be needed where there is doubt about the diagnosis, revealing abnormal infiltration by smooth muscle cells which can be identified by immunohistochemical staining for the HMB45 (human melanoma black) antigen. Aspirated pleural fluid may show diagnostic clusters of immature muscle cells.

Fig. 18.14.6.1 CT scan of a 37-year-old woman with pulmonary lymphangioleiomyomatosis and tuberous sclerosis. She had experienced sequential spontaneous pneumothoraces affecting each side. The scan shows multiple thin-walled cysts throughout the lung.

Fig. 18.14.6.1
CT scan of a 37-year-old woman with pulmonary lymphangioleiomyomatosis and tuberous sclerosis. She had experienced sequential spontaneous pneumothoraces affecting each side. The scan shows multiple thin-walled cysts throughout the lung.

LymphangioleiomyomatosisHormonal therapy with progesterone or tamoxifen is usually given to patients with progressive disease: there are reports of benefit, but clear evidence of effectiveness is lacking. Pneumothorax is common and likely to recur such that medical or surgical pleurodesis is advisable. Lung transplantation is the main option for patients with advanced LAM, but recurrence of the disease due to migration of LAM cells to the donor lung has been reported. Rapamycin (sirolimus) inhibits the protein mTOR and stabilizes lung function and reduces symptoms in selected patients, but there are concerns about its long term safety. The clinical course of LAM is variable, with about 70% survival 10 years after diagnosis. Although some patients with LAM have had uncomplicated pregnancies, the hormonal changes of pregnancy pose a risk of disease progression.

Further reading

Bissler JJ, et al. (2008). Sirolimus for angiomyolipoma in tuberose sclerosis complex or lymphangioleiomyomatosis. N Engl J Med, 358,140–51.Find this resource:

    Cudzilo CJ, et al. (2013). Lymphangioleiomyomatosis screening in women with tuberous sclerosis. Chest, 144, 578–85.Find this resource:

      Johnson SR, et al. (2010). European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis. Eur Respir J, 35, 14–26.Find this resource:

        Krymskaya VP (2012). Treatment options for pulmonary lymphangioleiomyomatosis: progress and current challenges. Am J Respir Cell Mol Biol, 46, 563–65.Find this resource:

          Websites

          LAM Action. Working for patients with lymphangioleiomyomatosis. http://www.lamaction.org/

          The LAM Foundation. A breath of hope. http://lam.uc.edu [Provides links to other LAM sites worldwide.]