Lymphangioleiomyomatosis (include discussion of Tuberous Sclerosis and Birt-Hogg-Dubé Syndrome)

What every physician needs to know:

Lymphangioleiomyomatosis (LAM) is a rare cystic lung disease that is associated with progressive dyspnea on exertion, recurrent pneumothorax, chylous thoracic and abdominal effusions, and thoracic and abdominal tumors, including lymphangioleiomyomas and angiomyolipomas. LAM occurs predominantly in young and middle-aged women, but it has also been reported in children, post-menopausal women, and men. Dyspnea-inducing LAM occurs almost exclusively in women.

LAM occurs in patients with tuberous sclerosis complex (TSC), an inheritable, variably penetrant, genetic disease associated with cognitive impairment, seizures, skin lesions, and benign tumors in multiple organs. This form of LAM, termed “TSC-LAM,” affects approximately 30-40% of females with TSC–more than 100,000 women worldwide. Approximately 10-15% of males with TSC have cystic changes in the lung, but here are fewer than five biopsy-documented cases of TSC-LAM in males in the literature.

LAM also occurs in patients who do not have TSC. This form, termed “sporadic LAM” or “S-LAM,” is diagnosed in at least 2.5-5 per million women, or roughly 10,000 women worldwide, although it is likely that S-LAM is substantially underdiagnosed. To date, only one biopsy-documented case of S-LAM in a male has been reported. Although less common, most patients seen in the clinic have S-LAM rather than TSC-LAM.

In LAM, lung destruction occurs as a result of neoplastic proliferation of benign-appearing smooth muscle cells in the lung. Genetic evidence indicates that the LAM cells that infiltrate the lung arise from an unknown extrapulmonary source and spread via the bloodstream and lymphatics. Leading candidates for the site of origin include the uterus, renal angiomyolipomas, and lymphatics. LAM cells express the lymphangiogenic growth factors VEGF-C and VEGF-D and induce disordered lymphatic channel formation in the lung and lymphatics. “Frustrated lymphangiogenesis” likely contributes to the extensive remodeling and cystic destruction of the lung.

The differential diagnosis of diffuse, thin-walled cystic change on high-resolution CT (HRCT) scan of the lung includes centrilobular emphysema; panlobular emphysema that is due to alpha one antitrypsin deficiency; pulmonary Langerhans cells histiocytosis; follicular bronchiolitis or lymphocytic interstitial pneumonitis; and Birt-Hogg-Dubé syndrome.

Less common LAM mimics that produce a diffuse cystic pattern on HRCT include include metastatic sarcomas and other malignancies; amyloid and nonamyloid immunoglobulin deposition disease; pneumatocele formation that is due to Pneumocystis jiroveci, Staphylococcus aureus, trauma, or barotrauma; lymphoma; hypersensitivity pneumonitis; desquamative interstitial pneumonitis; hyper IgE syndrome; recurrent respiratory papillomatosis; neurofibromatosis; Ehlers Danlos syndrome; Proteus syndrome; and Erdheim-Chester disease.

The European Respiratory Society has published guidelines for the diagnosis of LAM. An ERS-defined “definite diagnosis” is based on a characteristic or compatible HRCT and a lung biopsy that fits the pathological criteria for LAM. Positive immunohistochemical staining for HMB-45 in the correct histological context is highly specific for LAM. The ERS document states that a definite clinical diagnosis can be based on the presence of characteristic cystic change on HRCT and at least one of the following clinical features: tuberous sclerosis, chylothorax or chylous ascites, angiomyolipoma, lymphangiomyoma, or biopsy-documented lymph node involvement. An elevation of serum VEGF-D to greater than 800 pg/ml is also diagnostic for LAM in patients with typical cystic change on CT, based on a recently published American Thoracic Society and Japanese Respiratory Society LAM Guideline.

HRCT appearance alone is not sufficient to establish a definitive diagnosis of LAM, especially in cases when use of long-term therapies with toxicities is being considered.

Pneumothorax, which occurs in 70% of patients, tends to be recurrent. The LAM Foundation Pleural Disease Consensus Group recommends pleurodesis for the first pneumothorax to prevent morbidity associated with ipsilateral recurrences (which occur in 70% of LAM patients). The preferred method of pleurodesis is mechanical abrasion since talc and pleurectomy induce intense pleural fusion, which can complicate future lung transplantation. Even bilateral prior pleurodesis is not a contraindication for transplant in most expert centers.

A recent randomized controlled trial demonstrated that sirolimus stabilized lung function and improved some measures of quality of life and functional performance in patients with moderately severe LAM. However, the decision to treat must be individualized since safety and efficacy data beyond one year of treatment are lacking, and the sirolimus and other mTOR inhibitors have significant toxicities. Small case series and case reports also support the use of sirolimus in patients with problematic chylous effusions and lymphangiomyomas, and in patients with rapidly progressive disease referred for transplantation. Recommendations for the use of sirolimus can be found in the American Thoracic Society and Japanese Respiratory Society LAM Guidelines.

It is unclear whether asymptomatic patients with normal lung function who experience rapid lung function decline should be treated with mTOR inhibitors, but many LAM experts treat progressive disease before FEV1 or DLCO fall below 80% of predicted. The American Thoracic Society and Japanese Respiratory Society LAM Guidelines recommend against the use of hormonal therapy for LAM.

LAM is a slowly moving neoplasm. Prognosis varies widely in different populations. A population-based survey of all patients registered with the LAM Foundation using a National Death Index search revealed a median survival of more than twenty years. A study in the UK reported 10% mortality at ten years, while a study in Japan reported 40% mortality at ten years for patients who present with exertional dyspnea and 11% mortality for patients who present with pneumothorax.

Classification:

LAM is clinically classified as TSC-LAM and S-LAM according to the presence or absence of concomitant tuberous sclerosis, respectively, and as extrapulmonary or pulmonary according to location. There is no widely accepted method for categorizing the severity of LAM, but methods that are often used include descriptions of mild, moderate, and severe cystic change based on profusion of cysts on the HRCT; use of scales for severity of obstructive lung disease like the GOLD (Global Obstructive Lung Disease) criteria; and use of New York Heart Association Classification (NYHA) for functional performance and exercise tolerance (as also used in patients with pulmonary arterial hypertension).

Pathologically, LAM is classified as a perivascular epithelioid cell (PEComa) tumor along with clear cell carcinoma of the lung and angiomyolipomas.

Tuberous Sclerosis-Associated LAM (TSC-LAM)

LAM is closely linked with tuberous sclerosis complex, an autosomal-dominant, transmissible, variably penetrant genetic disorder associated with cognitive impairment, tumors, and dysplasias in multiple organs. Germ-line mutations are present in patients with TSC; approximately 33% of TSC patients have an inherited TSC mutation and a family history, but family history is absent in two-thirds of TSC patients, in whom TSC mutations occur during embryogenesis.

LAM that occurs in patients with TSC is termed “TSC-LAM.” Cystic changes consistent with LAM occur in about 30-40% of women and 12% of men with TSC. These changes appear to develop in a time-dependent manner in women with TSC, such that most women with TSC have some cysts by age forty.

It is estimated that there are over 100,000 TSC-LAM patients worldwide, based on a minimum estimated global prevalence of TSC patients of at least a million people (although estimates as high as two million people with TSC are also reported). Although the natural history of TSC-LAM has not been completely defined, clinically significant LAM appears to develop in only a small fraction of TSC patients with cystic change on CT – perhaps 5-10% or less – and almost exclusively in women.

Patients with TSC-LAM do not typically undergo lung biopsy because the diagnosis is generally made on clinical grounds. However, when tissue is available, TSC-LAM is indistinguishable from that which occurs in patients with S-LAM, other than the concomitant appearance of nodular proliferations of alveolar type II cells in TSC-LAM patients, known as multifocal micronodular pneumocyte hyperplasia (MMPH). MMPH has no reported prognostic or physiologic significance. Some TSC patients with cystic change on HRCT prove to have bland bullous and cystic change that mimics emphysema on biopsy without other characteristic features of LAM, suggesting that there are other mechanisms of cystic formation in TSC.

Sporadic LAM (S-LAM)

LAM also occurs in patients who do not have tuberous sclerosis; this form is termed “sporadic LAM” or “S-LAM.” Patients with S-LAM have TSC mutations in the involved lung tissue, kidney tissue, and lymph nodes, but not in normal portions of the involved organs or in circulating blood cells. (Very low numbers of disseminated LAM cells have been detected in blood using enrichment techniques and very sensitive genetic methods.) The location of TSC mutations suggests that, in S-LAM, TSC mutations occur in somatic tissues somewhere along the timeline from conception through adulthood. Alternatively, S-LAM could be a form of low level mosaicism for TSC gene mutations.

It is estimated that S-LAM occurs in about 5 per million women, or about 10-20,000 patients worldwide, but the disease is likely substantially underdiagnosed. S-LAM patients represent about 85-90% of LAM patients seen in adult pulmonary clinics, and the remaining 15% are TSC-LAM patients. It is unclear why the less prevalent disease, S-LAM, more commonly presents for medical attention than the less prevalent disease, TSC-LAM, but this could represent different natural histories for the two disorders. LAM is typically more progressive in pre-menopausal patients who have a reduction in FEV1 or 75-135 cc per year. Lung function decline occurs at approximately half that rate or less in post-menopausal patients. When matched for lung function impairment, TSC-LAM and S-LAM progress at the same rate.

Extrapulmonary LAM

Extrapulmonary LAM occurs when LAM is localized predominantly or exclusively in the abdomen and/or pelvis. Patients can present with extensive retroperitoneal adenopathy, cystic lymphangiomyomas, or chylous ascites that mimic malignancy, especially ovarian cancer or lymphoma. FDG-PET scanning can be useful in distinguishing LAM from these disorders since typical cancers are FDG-avid and LAM tissue is not. The natural history of extrapulmonary LAM is not clear, although early reports have suggested that progression to involvement of the lung is the rule.

Pulmonary LAM

In the thoracic cavity, LAM typically involves the lung, the pleura, and the mediastinal structures, leading to cystic remodeling of the pulmonary parenchyma, chylous effusions and pneumothorax, and mediastinal adenopathy. Cystic lymphangiomyomas can also develop in the chest. On occasion, lymphatic congestion can lead to a chylous interstitial edema that mimics pulmonary edema, including septal thickening and effusions. This condition can compromise gas exchange and present as an exacerbation.

There are no “stages” of LAM, but many clinicians classify severity based on typical spirometric criteria for severity of obstruction (FEV1>70% mild, 50-70% moderate, etc.).

Are you sure your patient has LAM? What should you expect to find?

The signs and symptoms of LAM are common to many lung diseases, and include dyspnea on exertion, pneumothorax, chylous effusions, abdominal tumors, and patients who also have TSC, skin lesions, and CNS findings.

Dyspnea on exertion

The most common presentation of LAM is progressive dyspnea on exertion. Although LAM is often mistaken for asthma or COPD, the absence of the distinct exacerbations and remissions that are typical for these obstructive disorders should trigger consideration of alternative diagnoses. In some patients, dyspnea may vary over the course of the menstrual cycle, reaching a peak near the commencement of flow.

Pneumothorax

Pneumothorax occurs in about 70% of patients with LAM, and ipsilateral recurrences occur in most patients. Patients who experience a sentinel pneumothorax have an average of 3.5 pneumothoraces in their lifetimes.

Primary spontaneous pneumothorax (PSP) is a common etiology of pneumothorax and is often the first consideration when a young woman presents with pneumothorax. In typical practice in the United States, HRCT is not usually obtained for initial pneumothorax in a patient without obvious underlying lung disease because it does not usually change PSP management. PSP typically occurs in tall, thin patients who smoke and is more common in males.

The prevalence of LAM in non-smoking women aged 25-54 who present with pneumothorax is predicted to be at least 5%, making a screening HRCT cost-effective in this population. In some patients, pneumothorax occurrence correlates with the phases of the menstrual cycle.

Chylous effusions

Chylous pleural effusions occur in about 30% of LAM patients. The primary differential in a young woman who presents with an apparently isolated chylous effusion is LAM, lymphoma, or trauma. Pleural fluid cytology may be helpful in distinguishing among these entities (see below). Chylous fluid collections may also appear in the abdomen (ascites) or pericardium.

Abdominal tumors

About 30% of patients with S-LAM and 80% of patients with TSC-LAM have renal angiomyolipomas. Angiomyolipomas are the only renal tumor masses that typically contain fat, so their radiographic appearance on CT and MRI is typically diagnostic, and no biopsy is necessary in most cases. Renal angiomyolipomas can vary in size from microscopic to over 12 cm in diameter and can become so bulky that diaphragmatic excursion can be compromised or early satiety and urinary urgency occur because of compression of hollow viscera in the abdomen. When renal angiomyolipomas are fat-poor, it is difficult to rule out renal cell carcinoma or other malignancy, and further diagnostic evaluation may be necessary.

As size exceeds a diameter of 4 cm, bleeding is more likely. The content of aneurysmal vessels also plays a role in the risk of bleeding. Embolization and radioablation are often used to reduce the size of angiomyolipomas and diminish bleeding risk. Partial nephrectomy is sometimes necessary, but complete resection is employed only as a last resort, in cases of life-threatening hemorrhage, or for the purpose of making room for a transplanted kidney.

Angiomyolipomas can also occur in the liver, the spleen, and (more rarely) the chest, including the mediastinum and pulmonary parenchyma. Cystic lymphangiomyomas, which occur in about 15-20% of patients with LAM, are lymphatic channels that become dilated because of proximal obstruction. They usually occur in the retroperitoneum and pelvis, and vary in size over the course of the day or with supine and erect body positions.

Skin lesions

Skin lesions occur in patients with TSC and TSC-LAM, but not in patients with S-LAM. Skin lesions can be useful in the differential diagnosis of LAM, and all patients with LAM should be examined by physicians who are familiar with skin findings of TSC and Birt-Hogg-Dubé syndrome. Angiofibromas on the face near the nose are common, as are hypopigmented lesions, including hypopigmented macules and ash leaf spots, on the trunk. Patients also develop periungual fibromas under the nails, confetti lesions on the extremities, and raised areas of rough skin called Shagreen patches. Other manifestations include streaking of the nails, pitting of the enamel of the teeth, and retinal hamartomas.

Central nervous system findings

Central nervous system findings are present in patients with TSC and TSC-LAM, but not in those with S-LAM. CNS-related symptoms may include seizures, cognitive impairment, and behavioral abnormalities. Structural abnormalities on MRI or CT of the head include cortical tubers, subependymal giant cell astrocytomas, and hydrocephalus. Meningiomas have been described in patients with S-LAM and TSC-LAM, but it is unclear to what extent therapies like progesterone may have contributed to the development of these lesions.

Other symptoms and signs

Respiratory tract manifestations of LAM may also include cough, vague chest pain, pleurisy, hemoptysis, and chyloptysis, and abdominal and pelvic manifestations can include bloating, chyluria, chylous vaginal discharge, chylous fluid in the stool, hematuria, and urinary urgency because of bladder compression from cystic lymphangiomyoma. Constitutional symptoms, including fatigue and asthenia, are common and incompletely explained.

Beware: there are other diseases that can mimic LAM:

The typical appearance of LAM on high-resolution CT scanning is characterized by diffuse cysts with walls 1-2 mm thick and no internal structure. The cysts are random in distribution, with no typical cranio-caudal or peripheral-central predominance. Mediastinal and hilar adenopathy, or pleural effusion may be present. Rarely, dilation of the thoracic duct may be seen. Ground glass is not part of the radiographic presentation of LAM unless lymphatic congestion is present. LAM tissue is does not accumulate FDG, and PET scans are negative.

Several diseases can mimic LAM based on similar appearances on high-resolution CT scanning. Emphysema, by far the most common mimic, occurs in smokers and is often apical-predominant. Cysts in this disorder have imperceptible walls and internal structures including vessels and septae. Pulmonary Langerhans cell histiocytosis also occurs in smokers. Cysts are typically apical in distribution (sparing the costophrenic angles), and are thicker-walled and more oddly shaped than LAM cysts. Ground-glass opacity, which is not seen in LAM in the absence of lymphatic congestion, may occur and the PET scan is often positive.

Follicular Bronchiolitis and Lymphocytic Interstitial Pneumonitis associated with Sjogren’s, Systemic Lupus Erythematosis, and Rheumatoid Arthritis are associated with cysts of varying sizes, and ground-glass infiltrates and a consolidated area may also be present. Cysts are usually thicker-walled than LAM cysts, have a blown-up appearance, and often contain internal structure and abut bronchovascular bundles. An “eccentric dot” that is due to an adjacent blood vessel is often present. Follicular bronchiolitis may present with cysts only and can closely mimic LAM.

Birt-Hogg-Dubé syndrome is characterized by thin-walled cysts that are typically basilar and peripheral (either central or lateral), and often lentiform in shape. Pathological evaluation reveals bland cysts, often within lymphatic septae, without smooth muscle infiltrate. Light Chain Deposition Disease, the appearance of which is similar to that of LAM, may be associated with monoclonal protein in serum and/or urine. Pathologic evaluation reveals interstitial expansion with non-amyloid proteinaceous deposits.

Cysts in Amyloid lung disease are often associated with nodules and ground glass. Congo red staining is positive. Cysts are a rare manifestation of Hypersensitivity pneumonitis, often in association with ground glass that is usually caused by exposure to fungus in the home or bird antigens. Desquamative interstitial pneumonitis occurs in smokers and is associated with ground-glass infiltrates and scattered cysts. Pneumatocele formation that is due to current or prior infectious illnesses, especially P. jiroveci and S. aureus is sometimes mistaken for LAM.

Certain metastatic malignancies, including endometrial stromal sarcoma, soft-tissue sarcoma, epithelioid sarcoma, low-grade leiomyosarcomas, and other genitourinary malignancies can produce thin-walled cysts in the lung. Recurrent episodes of Wegner’s granulomatosis or hypocomplementemic urticarial vasculitis can result in emphysematous or cystic changes.

Other very rare causes of multicystic disease include hyper IgE syndrome, respiratory papillomatosis, bronchopulmonary dysplasia, and barotrauma.

How and/or why did the patient develop LAM?

Current evidence suggests that LAM is due to mutations in tuberous sclerosis genes, is much more frequent in patients with TSC than in patients in the general population, is metastatic, occurs much more frequently in women than in men, arises from a unknown source, and spreads via the lymphatics and the bloodstream.

TSC is equally prevalent in men and women, so gender does not likely play a role in the development of mutations in TSC genes. TSC1 and TSC2 are large genes, which increases the risk of mutation, but there are no mutational hot spots–that is, mutations tend to occur randomly throughout the TSC genes. TSC2, the only known cause of S-LAM, is the most frequent cause of LAM in women with TSC, but TSC-LAM has been reported in patients with either TSC1 or TSC2 mutations. It is not clear whether other factors predispose patients to developing mutations in tuberous sclerosis genes.

LAM occurs in at least 30% of women with TSC and in .0003% of women who do not have TSC. Therefore, TSC increases the risk of LAM in women at least 10 million-fold. This increased susceptibility may be because, in patients with S-LAM, primary tumor development requires “two hits” in a somatic tissue (a rare event), whereas in TSC-LAM, one TSC allele is mutated in all cells of the body, and primary tumor development requires only the second “hit.” S-LAM may also be due to low-level mosaicism for TSC–that is, a fraction of all somatic cells contain TSC mutations, and the second hit results in primary tumor formation. This model may explain why patients with S-LAM often have angiomyolipomas and sclerotic bone lesions.

Two lines of evidence indicate that LAM is metastatic. First, the mutations that are found in the cells derived from the kidney and lung lesions in patients with S-LAM are identical, indicating a common origin. Second, LAM recurs in transplanted lungs; two laboratories have used genetics and immunohistochemistry to show that the cells in the recurrent lesion in the allograft arise from the recipient.

The fact that LAM occurs much more frequently in women than men could have an anatomic basis, a hormonal basis, or both. Hayashi and Seyama recently reported that LAM was found in the resected, step-sectioned uterus of three out of three sporadic LAM patients and in seven of eight TSC-LAM patients, and the profusion of LAM lesions was much higher in patients with TSC-LAM. Angiomyolipomas are another possible primary source in patients with LAM, but only about 30% of patients with sporadic LAM have an angiomyolipoma. It is also possible that estrogen contributes to LAM pathogenesis, based on evidence that estrogen stimulates MAP kinase signaling and downregulates apoptosis, and LAM appears to progress more slowly in women who are postmenopausal.

LAM cells that exhibit loss of heterozygosity for TSC1 and TSC2 have been isolated from the blood of patients with LAM. At autopsy, LAM cells are found infiltrating the walls of lymphatic channels and budding into the lumen. LAM cell clusters are also found in the chylous effusions in the chest and abdomen of patients with LAM. Seyama et al. proposed a theory in which LAM cells “leap-frog” up the lymphatic system by serial cycles of implantation and budding, are transported in lymphatic flow as lymphatic endothelial lined clusters of about 100 cells up the lymphatic duct, are delivered into the venous system in the neck, and impact in the pulmonary microvasculature. Once there, the cells infiltrate all structures of the pulmonary interstitium, including the blood vessels, lymphatics, and airways.

Which individuals are at greatest risk of developing LAM?

Patients with TSC are at increased risk of developing LAM. Therefore, patients with LAM should be screened for the presence of TSC, and patients with TSC should be screened for the presence of LAM. Establishing a diagnosis of TSC in a patient with LAM is important because familial transmission is possible in this subset of patients, and genetic counseling may be indicated.

Screening of LAM patients for the presence of TSC

All patients with LAM should be screened for the presence of TSC, at least by a physical exam that includes a dermatologic evaluation for angiofibromas, hypopigmented macules, Shagreen patches, and confetti lesions, and an ophthalmological evaluation that may reveal retinal hamartomas. Imaging, which can be particularly helpful in establishing or excluding a diagnosis of TSC, should be considered for patients with a family or personal history of cognitive impairment or seizures. Computed tomography (CT) or magnetic resonance imaging (MRI) of the brain may reveal subependymal nodules, cortical tubers, hydrocephalus, or subependymal giant-cell astrocytomas. CT or MRI of the abdomen may reveal angiomyolipomas, which, if they are large and bilateral, suggest TSC. Bone images may reveal areas of sclerosis, which are can be consistent with tuberous sclerosis complex, but which also occur rarely in S-LAM (perhaps consistent with the mosaicism theory of LAM pathogenesis).

Screening of TSC patients for the presence of LAM

Women with tuberous sclerosis should be screened for the presence of LAM by obtaining a high-resolution CT scan of the chest after age eighteen (ERS Guidelines and Tuberous Sclerosis Alliance recommendation). Scanning should also be obtained in women with TSC who subsequently develop respiratory symptoms (ERS Guidelines). In the absence of symptoms, CT scanning should be repeated at least once in the fourth decade of life (ERS Guidelines). HRCT scanning can be repeated more frequently in patients who have an initial negative scan–every five years or so. A follow-up HRCT in one or two years to determine the rate of progression, and every three to five years thereafter should be obtained for patients who have cystic changes on a screening scan.

Serum VEGF-D is elevated in women with TSC-LAM but not in women with TSC alone, which suggests that serum VEGF-D may be useful for the identification of women with TSC who should undergo screening by HRCT for LAM. However, this theory must be prospectively tested before VEGF-D screening can be formally recommended. If proven to be sensitive and relatively specific for the presence or risk of development of LAM, measurement of serum VEGF-D could substantially reduce the burden of radiation to which TSC patients are exposed over their lifetimes.

Males with TSC rarely develop symptomatic LAM, so screening is not recommended. However, HRCT scanning is recommended in males with TSC who developed unexplained respiratory signs and symptoms, including dyspnea and pneumothorax.

Screening of young, non-smoking women with initial pneumothorax

Primary spontaneous pneumothorax is the most common cause of pneumothorax in women who have no known underlying lung disease. However, Hagaman et al. estimated that about 5% of pneumothoraces in nonsmoking 25-54-year-old women are due to LAM. At that prevalence, HRCT screening of the chest in that demographic is recommended as cost-effective.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Serum VEGF-D levels of greater than 800 pg/ml in patients with typical cystic change on HRCT of the chest are diagnostic for LAM.

Blood tests that are useful to exclude diseases that are in the LAM differential include alpha one antitrypsin level, Sjogren’s antibodies (SSA/SSB), rheumatoid factor and anti-CCP, and urine and serum protein electrophoresis to exclude light chain gammopathies.

What imaging studies will be helpful in making or excluding the diagnosis of LAM?

The most useful study for the diagnosis of LAM is high-resolution CT scanning of the chest. Typical findings include bilateral, random, round, symmetric, diffuse, thin-walled cysts of widely varying size, from 1-45 mm. The profusion of cysts can vary widely. Other findings may include enlarged mediastinal or hilar lymph nodes, ground-glass opacities related to lymphatic congestion, or an enlarged thoracic duct. HRCT scanning of the chest for first pneumothoraces in non-smoking women aged 25-54 is cost-effective and should be obtained on presentation to the emergency room.

CT or MRI of the abdomen can be useful for identifying angiomyolipomas or lymphangioleiomyomas, which can help establish the diagnosis of LAM in patients with typical cystic change on HRCT. Angiomyolipomas, which are usually found in the kidneys, are often single, unilateral, and small in patients with S-LAM, while they are large, bilateral, and multiple in patients with TSC-LAM. Retroperitoneal lymphadenopathy is another common finding, albeit a nonspecific one, in patients with LAM, especially S-LAM. Lymph node centers may be hypodense and mimic other neoplasms, especially lymphomas.

LAM tissue is FDG-PET negative, so PET scanning is useful for excluding or evaluating other neoplastic processes that are considered in the differential of LAM.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of LAM?

Pulmonary function testing is useful in the evaluation of patients with suspected or confirmed LAM. Thirty-four% of 230 patients who participated in the NIH LAM Registry had normal spirometry, 57% had obstruction, 11% had restriction, 6.3% had hyperinflation, and 17% had a bronchodilator response. Low DLCO and evidence of air-trapping are often the earliest pulmonary function changes in patients with LAM. In populations reported from clinics, hospitals and trials, LAM is often more severe than in registry populations. In the MILES trial, for instance, the average FEV1 and DLCO were each about 50% of predicted compared to about 70% of predicted in the NHLBI Registry report.

In patients who are progressing rapidly, spirometry should be repeated every 3-6 months. In other patients, pulmonary function testing should be obtained every 6-12 months and should include lung volumes and diffusing capacity at least annually.

What diagnostic procedures will be helpful in making or excluding the diagnosis of LAM?

Transbronchial biopsy has reasonable yield – likely in the range of 40-80% – in patients with LAM. The safety of transbronchial biopsy has not been established with certainty, but it appears to be acceptable based on series from China and Italy.

Video-assisted thoracoscopic biopsy is the definitive study for the diagnosis of LAM. Typical pathologic changes include foci of smooth muscle cell infiltration of lung parenchyma, airways, blood vessels, and lymphatics, associated with areas of thin-walled cystic change. LAM lesions contain an abundance of cleft-like spaces lined with endothelial cells, which represent disordered lymphatic channels. LAM cells stain with vimentin, and desmin, but these are not typically used clinically; staining with HMB-45, estrogen receptors, progesterone receptors, and smooth muscle actin are helpful in achieving an accurate diagnosis.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of LAM?

Chylous effusions and ascites from patients with LAM contain globe-like clusters of LAM cells that can be useful in the cytologic diagnosis of LAM. HMB-45 staining is helpful in this regard. Percutaneous needle biopsy of retroperitoneal lymph nodes can also be useful in the diagnosis of LAM. HMB-45 staining is useful for validating the diagnosis on small tissue specimens.

Genetic analyses for TSC are commercially available, but genotype analysis is not usually necessary or clinically useful for the diagnosis or management of TSC or TSC-LAM. Genotype analysis is not currently feasible in patients with S-LAM because circulating leukocytes do not contain mutations in TSC genes, and the low number of circulating LAM cells that have been reported from the NIH are below the limit of detection for typical mutational analysis.

If you decide the patient has LAM, how should the patient be managed?

Drug Therapy-mTOR inhibitors

LAM usually progresses slowly, so there is usually ample time to assess the rate of disease progression in individual patients before making therapeutic decisions. Lung function should be monitored serially. Patients with moderate to severe disease, problematic chylous effusions or lymphangiomyomas, or progressive disease based on rapid decline in FEV1 or DLCO may be considered for therapy.

Treatment with sirolimus may be considered for patients with progressive, moderately severe LAM. This recommendation is based on a single double-blind, placebo-controlled trial, the MILES trial, in which eighty-nine patients were randomized to one year of therapy with sirolimus or placebo, followed by an observation year off therapy. Lung function declined by over 10% in the first year in patients in the placebo group, but lung function stabilized in patients who were given sirolimus at doses required to maintain serum levels between 5 and 15 ng/ml (2 mg per day in most patients). When the drug was stopped, lung function decline resumed in the sirolimus group and paralleled that of the placebo group.

Adverse events, especially mouth ulcers, skin rashes, and cholesterol elevation, were more common in the sirolimus group, but serious adverse events were balanced between the groups. The optimal dosing of sirolimus, and the risk and benefits of longer-term therapy with sirolimus remain to be defined. Although most side effects of sirolimus are reversible, abating when the drug is withdrawn, the threat of latent virus-related malignancy remains an incompletely defined concern.

Case series and individual case reports indicate that patients with problematic chylous effusions and lymphangiomyomas respond to therapy with sirolimus with reduction in fluid collection volumes and shrinkage of lymphatic tumors. Patients with rapidly progressive disease approaching lung transplantation also appear to respond to sirolimus.

Indications for mTOR inhibitor treatment outside of these three categories are less clear. In patients with slow rates of progression, such as 30-50 cc of FEV1 loss per year, watchful waiting may be a reasonable approach. The rate of lung function decline in post-menopausal patients is slower than that in pre-menopausal patients, so it is particularly important to establish trends in these patients before exposing them to therapy.

One of the more problematic clinical dilemmas concerns whether to offer sirolimus to young, asymptomatic women with normal lung function who experience rapid rates of loss of FEV1, in the range of 150-200 cc per year. Given that the benefits of sirolimus seem to persist only while the drug continues, the risks and benefits of long-term use have not been well studied, and the drug has significant toxicities, including the risk of latent malignancy, use of the drug in this population must be carefully considered. Trials are planned to better define indication for sirolimus use in asymptomatic patients.

Other therapies – antiestrogen therapies

GnRh agonist therapies and progesterone have been used for decades for the treatment of LAM. Small case series have reached disparate conclusions about the effectiveness of these approaches, and no controlled trials have been done. A large retrospective study that compared the rate of lung decline in LAM patients who were or were not treated with progesterone revealed no benefit of progesterone therapy. However, differences in the rate of decline in lung function in pre- and post-menopausal patients in prior case series and in MILES suggest that estrogen may play an important role in disease progression. The American Thoracic Society and Japanese Respiratory Society LAM Guidelines suggest that hormonal therapy not be used for the treatment of LAM.

Management of pneumothorax

Pneumothorax occurs in about 70% of patients with LAM, and recurrence is the rule. LAM patients who have sentinel pneumothorax have an average of 3.5 pneumothoraces in their lifetimes. Therefore, the LAM Pleural Consensus Group recommends pleurodesis on the first event to limit the morbidity associated with recurrent events.

The preferred method of pleurodesis is mechanical abrasion. Talc and pleurectomy should generally be avoided since the intense pleural fusion that occurs with these approaches can result in increased bleeding if transplant becomes necessary. Most patients with LAM who have undergone transplant for LAM have had prior pleurodesis, including more than half who have had bilateral pleurodesis, so these procedures are clearly not an absolute contraindication in expert centers. The MILES trial showed a trend toward reduction of pneumothoraces in the sirolimus group, but additional studies are needed to determine whether mTOR inhibitor therapy can reduce the frequency of pneumothorax.

Management of chylothorax-beyond mTOR inhibitors

Chylothorax occurs in about 30% of patients with LAM. Small chylothoraces can often be managed without intervention, but for larger effusions, mTOR inhibitor therapy has been shown to be effective in case reports and case series. Another option is octreotide therapy, which decreases splanchnic circulation and the rate of chyle formation. Case reports of successful response of chylothoraces of various etiologies (including LAM) to octreotide therapy have been published. For patients who fail pharmacologic therapy and who require repeated taps to alleviate shortness of breath, pleurodesis may be considered. We recommend advanced thoracic imaging in this subset of patients, including heavy T2-weighted MRI, dynamic contrast-enhanced magnetic resonance imaging, intranodal lymphangiography, and transabdominal thoracic duct cannulation with lymphangiography to determine the source of the leak and intervene with coil placement or embolization. In some cases, chylous pleural effusion results from chyle that leaks from a source in the abdomen and is pumped into the thorax by the bellows action of the chest. Long-term indwelling catheters that patients can drain on their own at home have also been used with benefit. A few case reports of placement of peritoneal-venous shunt have also been published.

Management of lymphangiomyomas

Lymphangioleiomyomas can produce symptoms of abdominal and pelvic pain, bloating, pressure sensations on the pelvic floor, and urinary urgency. Pharmacologic therapy of lymphangioleiomyomas with mTOR inhibitors appears to be quite effective based on small series. Octreotide therapy may also be considered. Lymphangioleiomyomas tend to increase in size with erect posture and over the course of the day, and assuming a supine posture can alleviate symptoms. In general, lymphangiomyomas should not be resected or biopsied because persistent chyle leakage can lead to problematic and persistent chylous ascites.

Other therapy

Oxygen should be provided to maintain saturations of greater than 90% during rest, exercise and sleep. Bronchodilators should be trialed in patients who have shortness of breath, and vaccinations for flu and pneumococcal pneumonia should be kept up to date. Attention to bone health should include periodic bone density scanning and use of calcium, vitamin D, and bisphosphonate therapy, as appropriate. Finally, pulmonary rehabilitation can be quite beneficial in this population who often have fewer co-morbidities than other patients with other chronic lung diseases such as COPD.

What is the prognosis for LAM patients managed in the recommended ways?

The rate of decline in lung function varies with the population being studied. In cohorts composed primarily of S-LAM patients, the rate of decline in lung function has varied from -75 to -134 cc per year.

Rate of decline in lung function

S-LAM

The average rate of decline in lung function for patients who enrolled in the MILES trial was -134 cc per year, or about 10% of baseline line lung function. The rate of decline in the premenopausal patients (-17 cc per month) was more than five times the rate of decline in post-menopausal patients (-3 cc/month). The rate of decline in FEV1 in LAM patients followed at the NIH as part of the NIH Registry was -75 cc per year; these patients’ responses may have been milder because the study design selected for patients who were able to travel a distance to the site, often by air. The rate of decline in FEV1 published by groups in Europe was -118 ml per year.

TSC-LAM

The natural history of lung function decline in patients with TSC-LAM is unclear. However, because screening is possible in this population, patients are identified very early in the course of the disease, at a point at which the rate of disease progression appears to be low. Formal studies are needed in this area. Only a small fraction of women with TSC – perhaps less than 10% – develop clinically significant lung disease. When patients are matched for FEV1, the rate of decline in patients with TSC LAM and S LAM is very similar.

Survival

The prognosis of LAM varies by population and mode of presentation. Using the National Death Index, patients who are registered with the LAM Foundation had a median survival of twenty-nine years from the onset of symptoms. In a Japanese study of 173 patients, the survival probability from onset of symptoms of patients who presented with pneumothorax at five, ten, and fifteen years was 95%, 89%, and 89%, respectively; for patients who presented with dyspnea on exertion, the survival probability was 85%, 60%, and 47% at five years, ten years, and fifteen years, respectively. In a study of fifty-seven patients in the United Kingdom, survival from the onset of symptoms at ten years was 91%. The effect of sirolimus use on survival and time to lung transplant is not yet clear.

What other considerations exist for patients with LAM?

Air travel is generally safe for patients with LAM. In a study from the NIH in which 281 patients with LAM were studied with CXR after traveling to that center, the incidence of pneumothorax was no greater with air travel than with ground travel. Patients with LAM should not board a plane when they are experiencing unexplained shortness of breath or chest pain. Patients with severe LAM and limited pulmonary reserves may be less able to tolerate a pneumothorax during flight and should be cautioned that they may be at increased risk for an adverse outcome.

There are no other restrictions on types or levels of activity levels, other than perhaps avoiding scuba diving to depths of greater than ten feet, or unless significant pulmonary hypertension is present.

There are no dietary guidelines or recommendations available for patients with LAM. Whether the phytoestrogens contained in soy and other foods can have a deleterious effect at serum levels that are achievable with food based substances is unknown, but the consensus is that it is very unlikely. Phytoestrogens may have a protective effect in patients with breast cancer.

The LAM Foundation (www.thelamfoundation.org) provides education and support for patients with LAM. LAM Foundation research, funded with monies raised by LAM families, has formed the basis for clinical trials.

The LAM Foundation has established LAM clinics around the United States that have the interest, resources, and expertise to provide high-quality, multidisciplinary care to LAM patients. The LAM Foundation Clinical Research Network is a subset of LAM clinics that participates in cooperative trials.

What’s the Evidence?

Three current reviews of LAM:

Taveira-DaSilva, AM, Steagall, WK, Moss, J.. “Lymphangioleiomyomatosis”. Cancer Control. vol. 13. 2006. pp. 276-85.

McCormack, FX.. “Lymphangioleiomyomatosis: a clinical update”. Chest. vol. 133. 2008. pp. 507-16.

Johnson, SR.. “Lymphangioleiomyomatosis”. Eur Respir J.. 2006. pp. 1056-65.

Five articles that describe the natural history of LAM:

Urban, T, Lazor, R, Lacronique, J. “Pulmonary lymphangioleiomyomatosis: a study of 69 patients”. Medicine (Baltimore). vol. 78. 1999. pp. 321-37.

Johnson, SR, Tattersfield, AE.. “Decline in lung function in lymphangioleiomyomatosis: relation to menopause and progesterone treatment”. Am J Respir Crit Care Med. vol. 160. 1999. pp. 628-33.

Taveira-DaSilva, AM, Stylianou, MP, Hedin, CJ, Hathaway, O, Moss, J.. “Decline in lung function in patients with lymphangioleiomyomatosis treated with or without progesterone”. Chest. vol. 126. 2004. pp. 1867-74.

Johnson, SR, Whale, CI, Hubbard, RB, Lewis, SA, Tattersfield, AE.. “Survival and disease progression in UK patients with lymphangioleiomyomatosis”. Thorax. vol. 59. 2004. pp. 800-3.

Crooks, DM, Pacheco-Rodriguez, G, DeCastro, RM. “Molecular and genetic analysis of disseminated neoplastic cells in lymphangioleiomyomatosis”. Proc Natl Acad Sci U S A. vol. 101. 2004. pp. 17462-7. (This article describes the identification of rare circulating LAM cells in the peripheral blood containing mutations in tuberous sclerosis genes.)

Two LAM guideline articles:

Johnson, SR, Cordier, JF, Lazor, R, Cottin, V. “European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis”. Eur Respir J.. vol. 35. 2010 Jan. pp. 14-26.

McCormack, FX, Gupta, N, Finlay, G.. “Official American Thoracic Society and Japanese Respiratory Society Clinical Practice Guidelines”. Lymphangioleiomyomatosis Diagnosis and Management.

These two studies were the first to reveal the role of tuberous sclerosis mutations in sporadic LAM:

Smolarek, TA, Wessner, LL, McCormack, FX, Mylet, JC, Menon, AG, Henske, EP.. “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.. vol. 62. 1998. pp. 810-5.

Carsillo, T, Astrinidis, A, Henske, EP.. “Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis”. Proc Natl Acad Sci U S A. vol. 97. 2000. pp. 6085-90.

These two articles describe the role of lymphangiogenesis in the pathogenesis of LAM:

Kumasaka, T, Seyama, K, Mitani, K. “Lymphangiogenesis-mediated shedding of LAM cell clusters as a mechanism for dissemination in lymphangioleiomyomatosis”. Am J Surg Pathol. vol. 29. 2005. pp. 1356-66.

Kumasaka, T, Seyama, K, Mitani, K. “Lymphangiogenesis in lymphangioleiomyomatosis: its implication in the progression of lymphangioleiomyomatosis”. Am J Surg Pathol. vol. 28. 2004. pp. 1007-16.

These two studies use genetic analyses to reveal the role of metastasis in the pathogenesis of LAM:

Karbowniczek, M, Astrinidis, A, Balsara, BR. “Recurrent lymphangiomyomatosis after transplantation: genetic analyses reveal a metastatic mechanism”. Am J Respir Crit Care Med. vol. 167. 2003. pp. 976-82.

Bittmann, I, Rolf, B, Amann, G, Lohrs, U.. “Recurrence of lymphangioleiomyomatosis after single lung transplantation: new insights into pathogenesis”. Hum Pathol. vol. 34. 2003. pp. 95-8.

Hayashi, T, Kumasaka, T, Mitani, K. “Prevalence of uterine and adnexal involvement in pulmonary lymphangioleiomyomatosis: a clinicopathologic study of 10 patients”. Am J Surg Pathol. vol. 35. 2001. pp. 1776-85. (This provocative paper suggests that the uterus may be the source of LAM cells that infiltrate the lung.)

Goncharova, EA, Goncharov, DA, Eszterhas, A. “Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation: a role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM)”. J Biol Chem. vol. 277. 2002. pp. 30958-67. (This seminal article was the first to reveal the constitutive activation of the mTOR pathway in the lung of patients with LAM.)

These three TSC animal studies provide key preclinical evidence for clinical trials:

Kwiatkowski, DJ, Zhang, H, Bandura, JL. “A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells”. Hum Mol Genet. vol. 11. 2002. pp. 525-34.

Lee, L, Sudentas, P, Donohue, B. “Efficacy of a rapamycin analog (CCI-779) and IFN-gamma in tuberous sclerosis mouse models”. Genes Chromosomes Cancer. vol. 42. 2005. pp. 213-27.

Kenerson, HL, Aicher, LD, True, LD, Yeung, RS.. “Activated mammalian target of rapamycin pathway in the pathogenesis of tuberous sclerosis complex renal tumors”. Cancer Res.. vol. 62. 2002. pp. 5645-50.

These three trials focused on the effect of sirolimus on angiomyolipoma volume, but lung function effects were also seen, especially in the Bissler trial:

Bissler, JJ, McCormack, FX, Young, LR. “Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis”. N Engl J Med. vol. 358. 2008. pp. 140-51.

Davies, DM, de Vries, PJ, Johnson, SR. “Sirolimus therapy for angiomyolipoma in tuberous sclerosis and sporadic lymphangioleiomyomatosis: a phase 2 trial”. Clin Cancer Res.. vol. 17. 2011. pp. 4071-81.

Dabora, SL, Franz, DN, Ashwal, S. “Multicenter phase 2 trial of sirolimus for tuberous sclerosis: kidney angiomyolipomas and other tumors regress and VEGF- D levels decrease”. PLoS One. vol. 6. 2011. pp. e23379

Avila, NA, Dwyer, AJ, Rabel, A, Moss, J.. “Sporadic lymphangioleiomyomatosis and tuberous sclerosis complex with lymphangioleiomyomatosis: comparison of CT features”. Radiology. vol. 242. 2007. pp. 277-85. (This study compares imaging findings between patients with S-LAM and those with TSC-LAM.)

These articles provide somewhat differing perspectives on the diagnostic utility of serum VEGF-D in LAM:

Young, LR, Vandyke, R, Gulleman, PM. “Serum vascular endothelial growth factor-D prospectively distinguishes lymphangioleiomyomatosis from other diseases”. Chest. vol. 138. 2010. pp. 674-81.

Glasgow, CG, Avila, NA, Lin, JP. “Serum vascular endothelial growth factor-D levels in patients with lymphangioleiomyomatosis reflect lymphatic involvement”. Chest. vol. 135. 2009. pp. 1293-300.

Ryu, JH, Moss, J, Beck, GJ. “The NHLBI lymphangioleiomyomatosis registry: characteristics of 230 patients at enrollment”. Am J Respir Crit Care Med. vol. 173. 2006. pp. 105-11. (This study describes the baseline characteristics of more than two hundred patients who enrolled in the National Institutes of Health Registry.)

McCormack, FX, Inoue, Y, Moss, J. “Efficacy and safety of sirolimus in lymphangioleiomyomatosis”. N Engl J Med.. vol. 364. 2011. pp. 1595-606. (This double-blind randomized clinical trial demonstrated that sirolimus stabilizes lung function in patients with LAM and improves some measures of quality of life and functional performance.)

Goldberg, HJ, Harari, S, Cottin, V, Rosas, IO. “Everolimus for the treatment of lymphangioleiomyomatosis: a phase II study”. Eur Respir J.. vol. 46. 2015 Sep. pp. 783-94. (In this open-label trial, everolimus appeared to stabilize lung function in patients with LAM.)

Taveira-DaSilva, AM, Hathaway, O, Stylianou, M, Moss, J.. “Changes in lung function and chylous effusions in patients with lymphangioleiomyomatosis treated with sirolimus”. Ann Intern Med.. vol. 154. 2011. pp. 797-805. (The most important findings of this observational study of patients who were treated with sirolimus based on clinical grounds and who were followed at the NIH were the durability of lung function improvement and the response of chylous effusions and lymphatic tumors to sirolimus over an average period of longer than two years.)

Neurohr, C, Hoffmann, AL, Huppmann, P. “Is sirolimus a therapeutic option for patients with progressive pulmonary lymphangioleiomyomatosis?”. Respir Res. vol. 12. 2011. pp. 66(Sirolimus stabilized and, in some cases, appeared to improve lung function in patients referred for lung transplant who were rapidly declining.)

Johnson, SR, Cordier, JF, Lazor, R. “European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis”. Eur Respir J. vol. 35. 2010. pp. 14-26. (These consensus guidelines for the diagnosis and management of LAM were the first to provide a standardized approach to the disease.)

These two studies provide survival and prognosis data:

Hayashida, M, Seyama, K, Inoue, Y. “The epidemiology of lymphangioleiomyomatosis in Japan: a nationwide cross-sectional study of presenting features and prognostic factors”. Respirology. vol. 12. 2007. pp. 523-30.

Johnson, SR, Whale, CI, Hubbard, RB. “Survival and disease progression in UK patients with lymphangioleiomyomatosis”. Thorax. vol. 59. 2004. pp. 800-3.

Hagaman, JT, Schauer, DP, McCormack, FX. “Screening for lymphangioleiomyomatosis by high-resolution computed tomography in young, nonsmoking women presenting with spontaneous pneumothorax is cost-effective”. Am J Respir Crit Care Med. vol. 181. 2010. pp. 1376-82. (This study presents the case for obtaining a HRCT on the first presentation of a young, non-smoking woman with pneumothorax.)

These studies describe a cytologic approach to the diagnosis of LAM based on the analysis of pleural fluid:

Mitani, K, Kumasaka, T, Takemura, H. “Cytologic, immunocytochemical and ultrastructural characterization of lymphangioleiomyomatosis cell clusters in chylous effusions of patients with lymphangioleiomyomatosis”. Acta Cytol. vol. 53. 2009. pp. 402-9.

Malinowska-Kolodziej, I, Finlay, G, Campbell, G. “Lymphangioleiomyomatosis: cause of a malignant chylous pleural effusion”. J Clin Oncol. vol. 28. 2010. pp. e4-6.

Young, LR, Franz, DN, Nagarkatte, P. “Utility of [18F]2-fluoro-2-deoxyglucose-PET in sporadic and tuberous sclerosis-associated lymphangioleiomyomatosis”. Chest. vol. 136. 2009. pp. 926-33. (This paper describes the utility of PET scanning in LAM.)

Gupta, N, Meraj, R, Tanase, D, James, LE. “Accuracy of chest high-resolution computed tomography in diagnosing diffuse cystic lung diseases”. Eur Respir J.. vol. 46. 2015 Oct. pp. 1196-9. (This paper describes the utility of HRCT alone in the dx of LAM.)

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