Lymphangioleiomyomatosis

Updated: Dec 22, 2019
Author: Joel Moss, MD, PhD; Chief Editor: Zab Mosenifar, MD, FACP, FCCP 

Overview

Background

Lymphangioleiomyomatosis (LAM) is a rare lung disease, resulting from proliferation in the lung, kidney, and axial lymphatics of abnormal smooth muscle–like cells (LAM cells) that exhibit features of neoplasia and neural crest origin.[1, 2, 3] Cystic destruction of the lung with progressive pulmonary dysfunction and the presence of abdominal tumors (eg, angiomyolipomas [AML], lymphangioleiomyomas) characterize the disease.

In 2015, the World Health Organization reclassified lymphangioleiomyomatosis with PEComa benign and malignant tumors in a new PEComatous tumors group. Previously, LAM was considered an interstitial lung disease but it is now considered to be a low-grade destructive metastasizing neoplasm.[4]

LAM is almost exclusively seen in adult women and occurs both sporadically and in patients with tuberous sclerosis complex (TSC), an inherited an autosomal dominant neoplastic syndrome due, in part, to mutations in the TSC1 or TSC2 gene.[5] Dyspnea with daily activities, recurrent pneumothoraces, and hypoxia requiring supplemental oxygen develop in most patients within 10 years of symptom onset.[6]

The 2017 American Thoracic Society/Japanese Respiratory Society guidelines support a clinical diagnosis of LAM based on high-resolution computed tomography (HRCT) findings typical for LAM (eg, diffuse, thin-walled, round) and accompanied by any of the following clinical features: TSC, renal angiomyolipoma, cystic lymphangioleiomyoma, or chylous pleural effusions in the chest and/or abdomen. The guidelines give a strong recommendation for the use of vascular endothelial growth factor D testing to establish the diagnosis of LAM before considering lung biopsy in patients with cystic abnormalities on HRCT characteristic of LAM, but no other confirmatory clinical features.[6]

Excellent patient resources can be found at the LAM Foundation and the National Heart Lung and Blood Institute.

Pathophysiology

Proliferation of lymphangioleiomyomatosis (LAM) cells may obstruct bronchioles,[1] possibly leading to airflow obstruction, air trapping, formation of bullae, and pneumothoraces. Obstruction of lymphatics may result in lymphangioleiomyomas, chylothorax, and chylous ascites. Excessive proteolytic activity, which relates to an imbalance of the elastase/alpha1-antitrypsin system or metalloprotease (MMPs) and their inhibitors (tissue inhibitors of metalloproteases [TIMPs]), may be important in lung destruction and formation of cysts.[7] Animal models suggest that estrogen may promote the metastasis of TSC2-deficient cells to the lungs.[8]

Lymphangioleiomyomatosis can be associated with micronodular type II pneumocyte hyperplasia, particularly in individuals with tuberous sclerosis. The TSC mutations that occur in LAM result in abnormal signaling through the mammalian target of rapamycin (mTOR) pathway.[4, 9]

The etiology of lymphangioleiomyomatosis (LAM) is unknown; however, the fact that the condition occurs primarily in premenopausal women and that it is exacerbated by high estrogen states suggests a role for hormones.

Epidemiology

LAM is almost exclusively seen in adult women affecting approximately 1 in 200,000[10] , but has also been reported in adult men[11] and children.[12] Sporadic LAM affects 1 in 400,000 adult females;[13] and in TSC, LAM occurs in 30–40% of adult females.[14] Although Europe and Japan report case series[10] , no racial predilection has been reported.

Prognosis

Earlier reports indicated a grim prognosis for lymphangioleiomyomatosis (LAM), with progressive respiratory failure and death within 10 years of diagnosis. Recent reports, however, are more favorable, with 71% of affected patients alive at 10 years.[15] The statistics may improve further as patients are diagnosed earlier (lead-time bias) or with more benign disease.

Poor prognostic factors include the following:

  • Reduced forced expiratory volume in 1 second and/or diffusing capacity for carbon monoxide[16, 17]

  • A low LAM histology score, which quantifies the involvement of the lung with both LAM cells and cysts[15]

Pneumothorax is a complication of LAM occurring in 40% of patients at presentation and 66% of patients during the course of the disease. The estimated rate of recurrence after the first episode is 75%.[13]

Angiomyolipomas are seen in 33-50% of patients with sporadic LAM and up to 80% of patients with TSC.[18] Angiomyolipomas usually manifest as multifocal, bilateral, asymptomatic disease, but as the lesions exceed 3 to 4 cm, they may become symptomatic and increase the risk for aneurysms that can lead to hemorrhage.[19]

Other complications of lymphangioleiomyomatosis (LAM) include the following:

  • Hemoptysis

  • Chylothorax

  • Ascites

  • Chyloptysis

  • Chyluria

  • Hematuria

  • Pericardial effusion

  • Pneumoperitoneum

  • Lymphedema

  • Respiratory failure

  • Osteoporosis

  • Meningioma

 

Presentation

History

Dyspnea and cough are common lymphangioleiomyomatosis (LAM) symptoms.[20] Less common symptoms (findings) are associated with pneumothorax and pneumoperitoneum, chylothorax and chylous ascites, and lymphedema.

Exacerbations of LAM have been reported to occur during pregnancy and menstruation, as well as with exogenous estrogen use.[21]

Physical

The examination in lymphangioleiomyomatosis (LAM) is often normal.

Less common findings include the following:

  • Crackles

  • Wheezes

  • Pleural effusion

  • Pneumothorax

  • Ascites

Signs of tuberous sclerosis complex[22] may be present, and include the following:

  • Facial angiofibromas

  • Periungual fibromas

  • Hypomelanotic macules, ash-leaf spots

  • Shagreen patch - A cluster of hamartoma typically located on the lower back

  • Forehead plaque

  • Retinal hamartoma

 

DDx

Diagnostic Considerations

Conditions with airways obstruction include the following:

  • Asthma

  • Spontaneous pneumothorax

  • Emphysema

Associations between lymphangioleiomyomatosis (LAM) and tuberous sclerosis complex (TSC) include the following:

  • TSC is a predisposing condition

  • Several shared clinical features (eg, cystic lung disease, angiomyolipoma [AML])

  • Shared genetic features: TSC2 gene mutations can be found in AMLs and lung lesions from patients with sporadic LAM.[23, 24]

Other conditions with pulmonary cysts, honeycombing, or interstitial pattern include the following:

  • Interstitial pulmonary fibrosis: Unlike LAM, lung volumes are reduced; however, patients with LAM who have had a pleurodesis may show decreased lung volumes.

  • Eosinophilic granuloma (EG): Lung volumes are increased, but large nodules may be found. Cysts in EG tend to have thicker walls than those in LAM.

  • Follicular bronchiolitis with or without lymphocytic interstitial pneumonia and Sjogren syndrome

  • Birt-Hogg-Dube syndrome

Lymphatic disorders include the following:

  • Diffuse pulmonary lymphangiomatosis

  • Lymphangiomas

  • Pulmonary lymphangiectasis

Conditions of abnormal smooth muscle proliferation in the lung include the following:

  • Leiomyosarcoma

  • Smooth-muscle proliferation in the lung

  • Benign metastasizing leiomyoma

 

Workup

Approach Considerations

Diagnostic Criteria

In its 2010 guidelines for diagnosis and management of LAM, the European Respiratory Society (ERS) proposed the following diagnostic criteria[13] :

LAM is considered associated with TSC (TSC-LAM) when TSC is present. Otherwise LAM is considered sporadic. A diagnosis is confirmed based on either:

  • Characteristic or compatible lung high-resolution computed tomography (HRCT), and lung biopsy fitting the pathological criteria for LAM; or
  • Characteristic lung HRCT and any of the following: angiomyolipoma (kidney); thoracic or abdominal chylous effusion; lymphangioleiomyoma or lymph-node involved by LAM; and definite or probable TSC .

A LAM diagnosis is probable based on either:

  • Characteristic HRCT and compatible clinical history that includes pneumothorax (especially multiple and/or bilateral) and/or altered lung function tests; or
  • Compatible HRCT and any of the following: angiomyolipoma (kidney); and thoracic or abdominal chylous effusion.

The criteria above is only for females. In males, LAM is very rare without TSC and rare with TSC; diagnosis requires both characteristic or compatible HRCT and typical pathological features on lung biopsy.

The 2017 American Thoracic Society/Japanese Respiratory Society guidelines support a clinical diagnosis of LAM based on HRCT findings typical for LAM (eg, diffuse, thin-walled, round) and accompanied by any of the following clinical features: TSC, renal angiomyolipoma, cystic lymphangioleiomyoma, or chylous pleural effusions in the chest and/or abdomen. The guidelines give a strong recommendation for the use of vascular endothelial growth factor D testing to establish the diagnosis of LAM before considering lung biopsy in patients with cystic abnormalities on HRCT characteristic of LAM, but no other confirmatory clinical features.[6]

Laboratory Studies

Vascular endothelial growth factor-D (VEGF-D) levels, above a certain threshold, are found in lymphangioleiomyomatosis (LAM) but not other cystic lung diseases. Hence, a serologic test for VEGF-D may be useful for diagnosis or follow-up.[25, 26] A prior study has shown that high levels of VEGF-D are associated with lymphatic involvement (eg, lymphangioleiomyomas, adenopathy) in LAM.[27, 28]

Imaging Studies

Chest radiographs in lymphangioleiomyomatosis (LAM) may be normal. Fine reticular or reticulonodular interstitial infiltrate with preserved lung volumes is the most commonly observed abnormality. Pleural effusions may be present. Patients may present with pneumothorax.

high-resolution computed tomography (HRCT) (HRCT) is the recommended imaging for the diagnosis of LAM. According to ERS guidelines, lung cysts are the defining lesion and appear in all patients with LAM. They typically range from 2–5 mm in diameter but can be as large as 30 mm. They are usually round and are distributed evenly throughout the lungs with normal lung parenchyma. Wall thickness ranges from barely perceptible to 2 mm but has been reported as measuring up to 4 mm.[13]

Other findings include the following:

  • Adenopathy and thoracic duct dilatation

  • Pleural effusion

  • Pneumothorax

  • Ground-glass opacities: May be present, perhaps representing alveolar hemorrhage or interstitial disease

  • Pericardial effusion

  • Multifocal multinodular pneumocyte hyperplasia (MMPH): Can be seen in patients with tuberous sclerosus complex (TSC), but the pathology is distinct from LAM

Abdominal imaging by either ultrasound or CT scan may demonstrate the following:

  • Angiomyolipoma (AML): Benign tumors (kidney, liver, spleen) containing smooth muscle, abnormal blood vessels, and mature adipose tissue

  • Retroperitoneal or mediastinal lymphangioleiomyomas

CT or MRI scanning of the head may reveal an incidental or symptomatic meningioma, which occurs with increased frequency in patients with LAM.[29]

On bone densitometry, patients with LAM exhibit accelerated osteoporosis.[30]

See Lymphangioleiomyomatosis Imaging for more information.

Other Tests

Pulmonary function testing, decreased diffusing capacity for carbon monoxide is the most common abnormality seen, and it is often markedly reduced.[20, 31] Hypoxemia at rest, worsening with exercise, is a common finding.[32]

On spirometry, airflow obstruction is the most frequent abnormality; restriction or mixed obstruction and restriction can also be seen.

Lung volumes may show an increased ratio of residual volume to total lung capacity.

Procedures

Histologic diagnosis can be made by performing an open lung, video-assisted thoracoscopic, or transbronchial biopsy (TBB)[33] ; the amount of tissue obtained from TBB may be insufficient to confirm a diagnosis. Lymphangioleiomyomatosis (LAM) cells react with human melanoma black (HMB)–45, an antibody generated against an extract of melanoma.[34] HMB–45 staining is used for the identification of LAM cells in biopsy specimans.

With classic high-resolution CT scans of the lung and associated findings of LAM (eg, tuberous sclerosis complex, angiomyolipoma, lymphangioleiomyomas), histologic confirmation may be unnecessary, especially if vascular endothelial growth factor D (VEGF-D) levels are elevated.[13]

Histologic Findings

Macroscopic pathology

Cysts are evenly distributed in all lung fields. Lymph nodes (retroperitoneal and pelvic) may appear pale and spongy; large chyle-filled cysts can be found within the axial lymphatic system. The thoracic duct may be large, spongy, and sausagelike.

Microscopic pathology

In histological sections of the lung, the following are observed[1] :

  • Proliferation of lymphangioleiomyomatosis (LAM) cells (spindle-shaped cells with small nuclei, larger epithelioid cells with clear cytoplasm and round nuclei) having a smooth muscle cell phenotype[35] These are usually found in the walls of the cystic air spaces, where their growth may be overt and nodular, although some cases may be very subtly infiltrative, to the extent that multiple levels are required to identify the lesional cells.[4]

  • Loss of alveoli with cyst formation

  • Aggregates of LAM cells abutting cystic spaces

  • Distal airway narrowing, thickened arterial walls with venous occlusion, and hemosiderosis

In involved lymph nodes and the thoracic duct, there are interlacing bundles of LAM cells, which may invade the walls of the lymphatics.

Immunohistochemical staining of LAM lesions demonstrates the following:

  • Reactivity with anti–alpha-smooth actin antibodies, which is consistent with smooth-muscle differentiation

  • S100-negative[4]

  • Estrogen and progesterone receptors

  • VEGF-D

  • Immunoreactivity with the monoclonal antibody HMB-45, which recognizes LAM cells with epithelioid features; rarely, spindle cells are also HMB-45 positive

  • Renal and hepatic AMLs, as well as lymphangioleiomyomas, can also be detected with HMB-45 antibody

 

Treatment

Approach Considerations

General care for patients with lymphangioleiomyomatosis (LAM) addresses the following findings[13] :

  • Pleural effusions - Consider chemical pleurodesis; surgical obliteration of the pleural space; medium-chain triglyceride (MCT [not a component of chyle]), lipid-free diet to reduce chyle flow (utility unknown)

  • Ascites - Paracentesis, MCT diet (utility unknown)

  • Airways disease and hypoxemia - Bronchodilators may be of benefit[16] ; supplemental oxygen, pulmonary rehabilitation, smoking cessation

  • Standard vaccination for respiratory infections

  • Osteoporosis - Standard surveillance and treatment; avoid exogenous estrogens[30]

  • Lung transplantation[36]

​Some reports suggest worsening of disease during pregnancy. Therefore, specialists generally recommend that caution be exercised when patients consider becoming pregnant. Despite the potential hazards, patients with mild disease have had uneventful pregnancies with little deterioration in lung function.

Medical Care

Sirolimus

In May 2015, sirolimus (Rapamune) was the first drug approved by the US FDA for LAM. It has demonstrated improvement in lung function in patients with LAM. Sirolimus also reduces the size of angiomyolipomas, lymphangioleiomyomas, and chylous effusions. The therapeutic response, however, is generally not sustained.[37, 38, 39, 40]

A clinical trial of 89 patients over 12 months showed patients taking Rapamune had a slower decline in lung function than those taking a placebo. After the drug was stopped, the decline in lung function resumed at the same rate as the placebo group.[37]

Hormone therapy

Possible options for hormonal manipulation include the following:

  • Medroxyprogesterone - Utility not known; recent case series does not support its use[41]

  • Gonadotropin-releasing hormone agonists - Utility not known; few case reports support their use

  • Tamoxifen does not appear to be effective[31] and is not recommended due to estrogen receptor agonist activity

  • Rate of decline in lung function trends to be less in postmenopausal women (eg, surgical oophorectomy, age)

Novel therapies

New experimental therapies include the following:

  • Chloroquine - Inhibitor of autophagy

  • Aromatase inhibitors - Antiestrogenic effects

Everolimus, an oral mTOR inhibitor, has been investigated as a treatment of renal angiomyolipoma associated with TSC or sporadic LAM.[42] A 4-year double-blind, placebo-controlled, phase 3 follow-up trial showed reduction in angiomyolipoma volume in 54% of patients.[19] During the extension phase of the study, 58% of patients achieved angiomyolipoma response. The most common adverse events reported were stomatitis (42%), hypercholesterolemia (30.4%), acne (25.9%), aphthous stomatitis and nasopharyngitis (each 21.4%).[18]

Surgical Care

Management of recurrent pneumothoraces or pleural effusions may require surgical intervention; in addition, patients with AML can develop complications (eg, hemorrhage), requiring intervention. Arterial embolization is favored over surgical resection.[43]

Consider lung transplantation for patients with end-stage pulmonary disease.

The Medscape Transplantation Specialty Center may be helpful.

Consultations

Pulmonologists can help establish the diagnosis and monitor pulmonary function. A pulmonologist can address issues such as vaccinations, oxygen therapy, and pulmonary rehabilitation. Consider patient referral to a center with expertise in lymphangioleiomyomatosis (LAM). Depending on disease severity, referral to a transplantation center may be beneficial.

AN endocrinologist and/or obstetrician-gynecologist may help address issues involved in hormonal manipulation therapy. An endocrinologist can assist with prophylaxis and treatment of osteoporosis in patients in whom exogenous estrogen is contraindicated. A urologist may assist with management of renal AML.

A dietitian may help to advise patients on medium chain triglyceride (MCT) diets for chylous ascites or pleural effusions.

Diet

Most patients with lymphangioleiomyomatosis (LAM) do not have special dietary requirements; however, if a patient is on antiestrogen therapies or is postmenopausal and not on estrogen replacement therapy, other cardiac risk factors relevant to diet (eg, cholesterol levels) should be addressed.

Although the use of rapamycin is favored, some patients with chylous effusions or ascites may try an medium chain triglyceride (MCT) diet (see Medical Care).

Activity

LAM is associated with reduced bone mineral density and osteoporosis. Weight-bearing exercise and strength training should be encouraged.[13]

 

Guidelines

Guidelines Summary

Guidelines for the diagnosis and management of lymphangioleiomyomatosis (LAM) have been issued by the following organizations:

  • European Respiratory Society (ERS)
  • American Thoracic Society (ATS) and Japanese Respiratory Society (JRS)

The European Respiratory Society's comprehensive guidelines were published in 2010. However, research advances have identified an effective treatment and a useful diagnostic biomarker since publication. In 2016, the American Thoracic Society (ATS) and Japanese Respiratory Society (JRS) released joint clinical practice guidelines which were endorsed by the LAM Foundation. Key recommendations based on evidence of varying quality include the following[6] :

  • Vascular endothelial growth factor D testing should be used to establish the diagnosis of LAM before considering lung biopsy in patients with cystic abnormalities on high-resolution computed tomography (HRCT) characteristic of LAM, but no other confirmatory clinical features or extrapulmonary radiologic features of LAM.
  • For patients with LAM with abnormal/declining lung function, treatment with sirolimus rather than observation is recommended.
  • For selected patients with LAM with problematic chylous effusions, treatment with sirolimus before invasive management is recommended.
  • Doxycycline and hormonal therapy should not be used for thetreatment of LAM.
 

Medication

Medication Summary

The goals of pharmacotherapy for lymphangioleiomyomatosis (LAM) are to reduce morbidity and to prevent complications. However, new drug therapies target the underlying disease.

Immunosuppressant agents

Class Summary

Immunosuppressants may inhibit T-lymphocyte activation and proliferation that come about from antigenic and cytokine stimulation.

Sirolimus (Rapamune)

LAM involves lung tissue infiltration with smooth muscle-like cells that harbor inactivating mutations of the tuberous sclerosis complex (TSC) gene (LAM cells). Loss of TSC gene function activates the (mechanistic target of rapamycin (mTOR) signaling pathway, resulting in cellular proliferation and release of lymphangiogenic growth factors. Sirolimus inhibits the activated mTOR pathway and thus the proliferation of LAM cells. It received FDA approval for treatment of LAM in May 2015. 

Antimalarials, Aminoquinoline

Class Summary

Aminoquinolines may inhibit prostaglandin effects.

Chloroquine Phosphate (Aralen)

Chloroquine is an autophagy inhibitor that appears to induce the death of TSC2-deficient cells when given in combination with sirolimus and is being tested in an ongoing clinical trial.

Anti-inflammatory activity results from lymphocyte transformation suppression. It inhibits chemotaxis of eosinophils and locomotion of neutrophils and impairs complement-dependent antigen-antibody reactions. Chloroquine may also have photoprotective effect.

Antineoplastics, Aromatase Inhibitor

Class Summary

Aromatase inhibitors can cause a significant reduction in plasma estrogen.

Letrozole (Femara)

Letrozole is an aromatase inhibitor with antiestrogenic effects that is being tested in LAM.

It is a nonsteroidal competitive inhibitor of the aromatase enzyme system. It inhibits the conversion of androgens to estrogens. Letrozole selectively inhibits gonadal steroidogenesis but has no significant effect on adrenal mineralocorticoid or glucocorticoid synthesis.

Patients treated with letrozole do not require glucocorticoid or mineralocorticoid replacement therapy.