Defining LAM

Lymphangioleiomyomatosis, or LAM , is an uncommon, progressive, cystic lung disease that predominantly affects young women. Pulmonary parenchymal changes consistent with LAM are found in about one third of women with tuberous sclerosis complex (TSC), an autosomal dominant tumor suppressor syndrome. LAM also occurs in a sporadic form that is not associated with germline mutations in TSC genes. Recent evidence that recurrent LAM after lung transplantation results from seeding of the graft from a remote source suggests a metastatic mechanism for the disease.

Characteristics of LAM

The most common presentation of LAM is progressive dyspnea on exertion, often in association with a history of pneumothorax or chylothorax. (Other symptoms of LAM include chest pain and coughing.) The histopathological hallmarks of the disease are dilated distal airspaces and diffuse infiltration of the pulmonary interstitium with atypical smooth muscle cells, including spaces surrounding airways, vessels, and lymphatics. The differential diagnosis of the thin walled cystic change that is characteristic of LAM also includes emphysema, Langerhan's cell histiocytosis, lymphocytic interstitial pneumonitis, Birt Hogg Dube syndrome, and Sjogren's syndrome. Rare syndromes of benign or malignant smooth muscle metastasis may also produce cystic change and closely mimic LAM, including benign metastasizing leiomyoma, endometrial stromal sarcomas, and low-grade leiomyosarcomas.

Renal Angiomyolipomas

Kidney tumors called angiomyolipomas, unusual hamartomas containing fat, smooth muscle and blood vessels, are present in about 70-80% of patients with TSC and 50% of sporadic LAM (Table 1). Hemorrhage into an angiomyolipoma can produce symptoms from chronic intermittent flank pain to acute abdomen with hypovolemic shock. Embolization or cauterization may be required to prevent bleeding, which may be more common in tumors that exceed 4 cm. in diameter (Table 2). Nephron-sparing partial resections may be required for very large tumors

Understanding the Epidemiology of LAM

LAM occurs almost exclusively in women. Cystic radiographic changes in men with TSC have been described in some TSC series, but only two biopsy documented cases of TSC-LAM have been reported in men. Sporadic LAM (S-LAM) has never been reported in a man. All races are affected. In one LAM Foundation survey of 480 patients, Caucasians made up 90%, Asians 3.5%, African Americans 3%, and Hispanics, 2%. TSC does not differentially affect particular ethnic groups, and access to health care, education, and the internet likely play important roles in the skewed ethnic distribution for LAM reflected in The LAM Foundation database.

The prevalence of S-LAM is roughly estimated to be approximately 3-5 per million people (30,000-50,000 patients worldwide), based on organized attempts to identify LAM patients in England, the United States and France by saturation mailings to all pulmonary physicians identified in each country. The incidence of TSC-LAM can be calculated from population data (Table 1). TSC occurs in approximately 1/6000 births, and the estimated number of TSC patients on earth is about 1-2 million. The worldwide prevalence of TSC-LAM therefore most likely falls in the range of 180,000 to 240,000 people, given the equal gender distribution of TSC and recent findings that 30-40% of women with TSC have cystic changes consistent with LAM.

Although TSC-LAM appears to be roughly 6-8 times as common as S-LAM, patients with TSC-LAM represent only a small fraction of the LAM patients seen in pulmonary clinics.

Approximately 13% of the 832 patients registered with The LAM Foundation (as of 9/2004) reported a history of TSC. Furthermore, LAM is a major clinical problem in only about 5% of TSC patients and is a primary health priority for only a few (<10) of the 300 patients in the Tuberous Sclerosis Clinic at the University of Cincinnati. There are several possible explanations for the low visibility of TSC-LAM patients in the LAM community, including that other TSC-related health priorities may overshadow pulmonary symptoms or that TSC-LAM behaves differently from S-LAM. Although screening of asymptomatic women with TSC will provide a mechanism to study the natural history of LAM, we must remain cognizant that TSC-LAM and S-LAM may not be exactly the same diseases.

Table 1. Comparison of TSC-LAM and Sporadic LAM

TSC-LAM

Sporadic LAM

Abbreviations:

• CNS; central nervous system
• MMPH; Multifocal micronodular pneumocyte hyperplasia

Table 2. Recommended interventions, studies and immunizations in patients with LAM

Clinical Presentation of LAM

The average age at diagnosis of S-LAM is about 35 years, after an average symptomatic period of 3-5 years. However, more recent reports include patients ranging from age 12-75 years. Most women registered with the Foundation complained of dyspnea on exertion (51%). Symptoms of cough (6%), chest pain (5%), hemoptysis (5%), chyloptysis and wheezing were all less common. Pneumothorax occurs in 66% of registered LAM patients at some point in the course of their illness, with slightly more episodes on the right side than the left. First recurrences after an initial pneumothorax occurred in more than 70% of patients, and contralateral pneumothoraces were almost as common. Thus, once a LAM patient has had a pneumothorax, a second event is more likely than not. Chylothorax occurs in about 33% of LAM patients at some point in the illness. Angiomyolipomas are present in most patients with LAM, including 70-80% of patients with TSC-LAM and 40-50% of patients with S-LAM. Rarely, LAM presents as retroperitoneal masses or adenopathy which mimic lymphoma, ovarian or renal cancer, or other malignancy. Large lymph filled abdominal lymphangiomyomas have also been described, and may vary in size with gravitational influences in supine and erect patients. Chest HRCT screening of asymptomatic TSC patients identifies a population with fewer and less severe pulmonary manifestations, including lower incidence of associated manifestations of chylous pleural effusions, pneumothoraces, hemoptysis and chest x-ray and lung function abnormalities. Ascertainment bias almost certainly plays a dominant role in the differences in disease manifestations that have been described for TSC-LAM and S-LAM in the literature.

Laboratory Findings

There are no consistent laboratory findings that are helpful in the diagnosis or management of LAM. There have been isolated case reports of serum elevations in CA-125, which can lead to a misdirected search for ovarian carcinoma. Although TSC1 and TSC2 genotype analysis is commercially available through Athena Diagnostics, mutations are not present in peripheral blood cells from S-LAM patients and the clinical utility of genotyping TSC-LAM patients has not yet been established.

Pulmonary Physiology

Lung function may be normal in LAM, especially in TSC-LAM patients identified through screening. LAM commonly presents with reductions in FEV1 out of proportion to reduction in FVC, consistent with obstructive physiology. Reversible airflow obstruction is present in up to 20-25% of patients. Elevations in RV and the ratio of RV/ TLC consistent with air trapping are frequently noted. Hyperinflation may also occur, which is unusual among the interstitial lung diseases. Mixed physiologic defects with superimposed restrictive changes are not uncommon, but it is unclear to what extent prior surgeries and pleural symphysis procedures may contribute to restrictive physiology. Impaired gas exchange and hypoxemia occur, but hypercapnea is rare even in end stage disease. Diffusion capacity for carbon monoxide (DLCO) is frequently reduced, and in some cases may be reduced out of proportion to the obstructive defect.

Radiology

The chest radiograph in LAM can be surprisingly unremarkable, even in the presence of moderately advanced disease. Basilar reticulonodular changes are not uncommon, and lung volumes can be normal or increased. Cystic and bullous changes, pleural effusions (unilateral or bilateral), hilar and mediastinal adenopathy and pneumothoraces may be apparent. High resolution CT scanning of the chest is the most helpful radiologic modality in LAM, and usually demonstrates profuse thin walled cysts in all lung fields (Figure 1). Diffuse nodular changes consistent with micronodular pneumocyte hyperplasia may be present predominantly in patients with TSC LAM. Abdominal CT scanning is positive in over 75% of patients, and may reveal fat containing renal or extrarenal angiomyolipomas, axial lymphadenopathy, cystic or noncystic lymphangiomyomas or chylous ascites (Figure 2). CT or MRI scanning of the brain is recommended at least once in the lifetime of all S-LAM patients to rule out findings of subclinical TSC such as cortical tubers, subependymal nodules or subependymal giant cell astrocytomas (Figure 3).

Figures

Figure 1. High resolution CT scan of the chest in a patient with LAM. Note the diffuse replacement of the pulmonary parenchyma with thin walled cysts.

Figure 1

Figure 2. Abdominal CT scan in a LAM patient with an angiomyolipoma. Note the diffuse involvement of the right kidney with an angiomyolipoma. Observe solid and fat density which is characteristic of angiomyolipomas.

Figure 2

Figure 3. CT scan of the head in two patients with tuberous sclerosis. Subependymal nodules are present in panel a. Cortical tubers are present in panel b.

Figure 4. Pathological features of LAM. Normal lung tissue with type II cells stained with antibody to surfactand protein A is shown. In panel b, an alveolar septal wall is expanded with spindle shaped and Epithelioid LAM cells. HMB 45 staining is shown in panel c. Cystic remodeling of the pulmonary parenchyma is shown in panel d.

Pathology

Grossly, the lungs are enlarged and diffusely cystic, with dilated airspaces as large as 2.0 cm in diameter. Microscopic examination of the lung reveals foci of smooth muscle cell infiltration of the parenchyma, airways, lymphatics, and blood vessels associated with areas of thin-walled cystic change (Figure 4). There are two major cell morphologies in the LAM foci, small spindle shaped cells in the center, and more cuboidal epitheliod cells in the periphery. LAM cells stain positively for smooth muscle actin and desmin. The lesions also react with a monoclonal antibody, HMB-45, developed against the premelanosomal protein gp-100. This immunohistochemical study is very useful diagnostically, since other smooth muscle predominant lesions in the lung do not react with the antibody. Unlike the dilated airspaces in emphysema, the cystic spaces are uniformly lined with hyperplastic type II cells. Diffuse nodular proliferation of type II cells called micronodular pneumocyte hyperplasia (MNPH) may occur in patients with TSC, in the presence or absence of LAM.

Diagnosis

Diagnostic dilemmas in LAM fall into two major categories; 1) How to identify LAM with progressive dyspnea and/or pneumothorax, 2) How to make the diagnosis of LAM in a woman with diffuse cystic changes on a CT scan of the chest with or without other corroborating evidence of LAM or TSC. The first scenario presents major challenges; how do we identify a rare , life threatening disease in a sea of common, less morbid obstructive diseases such as asthma and COPD. LAM is not usually part of the differential diagnosis for emergency and primary care physicians faced with a dyspneic patient, nor is it realistic to think that it will become so in the foreseeable future. Physical examination of the thorax and the chest radiograph can be surprisingly devoid of clues. Even severe cystic disease can be radiographically invisible on a chest radiograph. We submit that high resolution CT scanning should be obtained on all young nonsmoking women who present with dyspnea and a history of pneumothorax. While it is true that primary spontaneous pneumothorax (PSP) is a more common cause of pneumothorax in young females than LAM, PSP is almost always associated with tobacco use.

Although pneumothorax can also occur in the setting of asthma, these patients have significant bronchial hyperreactivity and characteristic relapsing/remitting bronchospasm.

The diagnosis of LAM occurs to most pulmonary physicians when pneumothoraces recur, occur in patients with TSC, or occur in a patient with chylothorax. High resolution CT scanning of the chest is routinely performed once the diagnosis is considered. Interpretation of the HRCT by expert radiologists leads to the correct diagnosis of LAM about 80% of the time. Diagnostic accuracy of 80% is not adequate in the setting of a life threatening lung disease, however, when deciding whether to perform a lung biopsy, the physician must determine if the clinical context is sufficiently compelling to make a clinical diagnosis without a biopsy. A full history including smoking, use of birth control pills, seizure history and family history of TSC should be obtained. Physical evidence of tuberous sclerosis should be sought, including acne-like angiofibromas-like lesions on the face, subungual fibromas, Shagreen's patches, ash leaf lesions, and other hypomelanotic lesions that fluoresce under the Wood's lamp such as confetti lesions. An abdominal CT or ultrasound to identify renal or extrarenal angiomyolipomas should be obtained if the abdominal cuts of the chest CT are inadequate. CT or MRI of the head should be considered for cortical tubers or other clinically occult manifestations of TSC. An a1 antitrypsin level should be sent to screen for hereditary forms of emphysema, and serologies for Sjogren's syndrome considered if xerostomia and xeroopthalmia are present.

In the setting of a compatible HRCT and specific corroborating clinical features, such as chylothorax, known TSC, or the presence of an angiomyolipoma in the kidney, the diagnosis of LAM can be made with certainty and lung biopsy is often not necessary. Lung biopsy should be considered when pulmonary cystic change is present without other clues, unless lung transplantation is imminent, in which case knowing the precise cause of the end stage lung disease is not usually critical. Video assisted thoracoscopic lung biopsy is the preferred method if pathologic confirmation is indicated. Transbronchial biopsies have occasionally been reported to be diagnostic in LAM when HMB-45 staining is positive.

Determining the Proper Therapeutic Strategy

Although patients with LAM have been managed empirically with antiestrogen therapies, there is no proof that these strategies are effective. Many clinicians do not treat asymptomatic LAM patients. Therapies that are currently discussed with patients who suffer progressive decline in lung function include progestins (both oral and intramuscular) and GnRH agonists. Doses of oral progestins that are sufficient to suppress serum estrogen production (e.g., Agestyn 10 mg po qd to bid) are suggested rather than the suprapharmacologic intramuscular progesterone doses that have been propagated in the literature (e.g., Depoprovera 400 m IM q month). Progestins can cause fluid retention and mood swings. Gonadotropin releasing hormone agonists (e.g.-Lupron) have been used in patients with LAM, but benefits are unproven and induction of early menopause is distressing and morbid in young women. There is no proven role for corticosteroids, immunomodulatory cytoxic agents or ovarian irradiation in the treatment of LAM. Oophorectomy is no longer recommended because the benefits are unknown and the risk of bone and heart disease is increased. In the face of therapeutic uncertainty, the patient and physician should make all treatment decisions jointly, after thorough discussion of the risks and limited available data.

Estrogen containing medications should be discontinued (Table 2). Patients should be advised that pregnancy has been reported to result in exacerbations of LAM and pneumothorax. However, the risk of pregnancy in LAM has not been rigorously studied. The physician and patient should discuss the risks of pregnancy carefully and decisions should be made on an individual basis.

Patients with LAM should avoid exposure to tobacco smoke.

A trial of bronchodilators should be considered in patients with LAM. Based on extrapolation from the COPD populations, the use of oxygen may prolong life in hypoxic patients with LAM. Oxygen should be administered to maintain oxyhemoglobin saturations of greater than 90% with rest, exercise and sleep. Bone densitometry should be considered in all patients who are immobilized and/or on antiestrogen therapies (Table 2). Calcium and bisphosphonate therapy should be considered in osteoporotic patients. Proper attention should be paid to cardiovascular health in patients who are rendered menopausal by therapy.

Pulmonary rehabilitation seems to be particularly rewarding in this young, motivated population, but studies that document improvements in exercise tolerance have not been done.

Many patients with LAM avoid air travel. Of 400 patients who responded to the LAM Foundation enrollment questionnaire, eight reported an episode of pneumothorax during air travel. In four cases, there was some evidence that the pneumothorax was present at the time the patient boarded the plane. Of over two hundred LAM patients who have been flying to and from the NIH clinical study for LAM, there have been no adverse events during air travel. It is wise to obtain a CXR prior to boarding a plane if pleuritic chest pain or unexplained persistent shortness of breath is present.

Pleural disease should be aggressively managed. Over 65% of patients with LAM develop pneumothorax and the average number of pneumothoraces per LAM patient is 3.5 (Table 1). The use of a pleural symphysis procedure is recommended on the first pneumothorax, given the >70% chance of recurrence. Chemical pleurodesis (preferably with talc), mechanical abrasion, talc poudrage and pleurectomy have all been effective in patients with LAM. Chyle does not cause pleural inflammation or fibrosis, and small chylous effusions most often require no intervention once the diagnosis is made. Shortness of breath may mandate drainage, however; and in some cases repeatedly. Pleural effusion may be required to prevent nutritional and lymphocyte deficiencies that can result from repeated taps or persistent drainage. Chemical pleurodesis is an effective alternative for chylothorax from other etiologies.

Referral for lung transplantation should be considered as FEV1 approaches 30% of predicted (Table 2). Some patients qualify based on other factors that profoundly affect quality of life, such as disabling dyspnea or problems maintaining oxygen saturation with lesser degrees of airflow obstruction, however. Bilateral lung transplantation produces slightly better functional outcomes in other obstructive lung diseases, but is not always feasible due to the limited availability of organs and urgency of the need for transplant. LAM patients should avoid exposure to tobacco smoke, discontinue estrogen-containing supplements, and become informed about the potential risks of pregnancy (Table 1).

Background on Lam

Lymphangioleiomyomatosis is a rare, cystic lung disease that is characterized by diffuse infiltration of the pulmonary parenchyma with histologically benign smooth muscle-like cells. LAM occurs almost exclusively in women, but clinical presentations consistent with LAM and biopsy-confirmed disease have also rarely been reported in men. The true incidence and prevalence of LAM are not known, but registry-based efforts to locate LAM patients in the United States, France, and the United Kingdom have identified approximately 750, 80 and 60 patients respectively, suggesting a minimum prevalence of 2-6 per million women. Patients with LAM suffer a relentlessly progressive course of dyspnea on exertion, frequently punctuated by recurrent pneumothoraces and chylous pleural effusions. After an average age of onset of 35 years. LAM has previously been managed with anti-estrogen therapies, based largely on the observed gender restriction and reports that birth control pills and pregnancy can worsen the disease, but there is no conclusive evidence that these strategies are effective. Because LAM mimics asthma and is often radiographically undetectable in early stages, the diagnosis is often delayed. The majority of the patients in the published retrospective clinical series of LAM presented with dyspnea with routine activities; an advanced irreversible, fibrotic stage when pulmonary reserves are exhausted and therapeutic interventions are disappointing. The design of definitive clinical trials to determine the effectiveness of empiric and experimental therapies would be greatly facilitated by the identification of patients in greater numbers and in earlier stages of their illness.

LAM occurs sporadically in patients without other evidence of genetic disease (sporadic or S-LAM), and also in patients with tuberous sclerosis (TSC-LAM). Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome characterized by hamartomatous growths in multiple organs including skin, eye, kidney and central nervous system. TSC is known to result from mutations in one of two tumor suppressor genes; the hamartin gene (TSC1) on chromosome 9, and the tuberin gene (TSC2) locus on chromosome 16.

The incidence of TSC-LAM has been estimated at 0.1-1% of TSC patients in a review of cases in the literature through 1971, and 2.3% of TSC patients that presented to the Mayo Clinic over a 43 year period, but a recent retrospective analysis of abdominal and chest CT scans indicated that LAM may affect up to 30% of women with TSC. Two recent prospective series indicate that up to 40% of women with TSC have cystic changes consistent with LAM. Based on these data, and the estimated prevalence of tuberous sclerosis, there may be as many as 8,000-10,000 TSC patients with LAM in North America and 250,000 TSC-LAM patients worldwide.

Familial TSC results from inheritance of germ line mutations, but de novo mutations account for 2/3rds of TSC cases. TSC-LAM can result from mutations in either TSC1 or TSC2. Mother-daughter transmission of TSC-LAM, but not S-LAM, has been reported. Chest x-ray and lung function abnormalities had been reported to be similar in the two diseases, as are the incidence of associated manifestations of chylous pleural effusions, pneumothoraces, and hemoptysis, but screening of asymptomatic TSC patients identifies a population with fewer and less severe pulmonary manifestations. Indeed, it is estimated that only about 5% of TSC patients with pulmonary cystic changes have respiratory symptoms. Angiomyolipomas, which occur in approximately 66% of patients with TSC, are found in up to 47-60% of patients with sporadic LAM.

The histologic appearance of TSC-LAM has not been rigorously compared to that of S-LAM. However, in both cases, smooth muscle cell infiltration of the lung parenchyma, airways, lymphatics, and blood vessels is associated with multiple thin-walled cysts. Comparison survival data for S-LAM and TSC-LAM are not available, but LAM is the third most common lethal complication of TSC. Based on their many clinical and pathological similarities, S-LAM and TSC-LAM are thought to share a common genetic and pathophysiologic basis.

Recent findings indicate that some, if not all, cases of S-LAM are due to mutations in TSC genes. Smolarek et al reported loss of heterozygosity (LOH) for TSC2 in AMLs and lymph nodes from patients with S-LAM, but TSC mutations are not found in the circulating blood cells from S-LAM patients. Carsillo et al subsequently demonstrated the presence of missense and protein truncating mutations associated with LOH in the lesional lung and kidney tissue of patients with S-LAM. Interestingly, in each of the patients with tissue available from both kidney and lung, the same mutation was found in both locations, but no mutations were found in the normal tissue from either organ. The authors proposed a model for LAM in which two somatic mutations in TSC2 cause disease, rather than the classic TSC paradigm of one germ line mutation and one somatic mutation. They also speculated that the lung infiltration and cystic destruction in LAM are a consequence of benign metastasis of LAM cells from the kidney tumor or axial lymph nodes, although they acknowledged that these data could also be consistent with low level mosaicism that was not detected by the mutation detection technique that was employed. Female TSC patients with lung cysts more frequently have a history of large angiomyolipomas requiring intervention than do cyst-negative patients, suggesting AMLs as a potential source. The recurrence of LAM in the donor lung of LAM patients who have undergone lung transplant is consistent with the metastatic theory. Although in two studies the proliferating lesional cells appeared to be of donor origin based on immunohistochemistry with a Y-chromosome probe, more sophisticated genetic analyses of the recurrent LAM lesion in one of those cases proved that the LAM cells were derived from the recipient. Other rare diseases which result from metastases of benign smooth muscle cells in women include leiomyomatosis peritonealis disseminata and benign metastasizing leiomyomatosis. The metastatic theory of LAM, which is both novel and provocative, suggests new avenues for treatment based on early intervention. This is clearly an area that is worthy of further study.

Fig. 1. Comparison of the phenotype of gigas and wild type Drosophila

Enlarged eye cells in TSC2 mutation-bearing gigas flies (B) compared to wild type flies (A) are shown. Phase microscopy reveals differences between normal pigmented wild type eye cells (C, upper left), compared to enlarged, nonpigmented cells (C, lower right). Bristles (D) arising from cells at the anterior edge of the wing are larger in those containing gigas mutations. (E) Photomicrographs of cells in the wing reveal enlargement in those containing the gigas mutant compared to wild type (36).

There has been truly remarkable progress in LAM research in the past two years, in some cases arising from quite unexpected sources. Drs. Ito and Rubin reported that the enlarged eye cells of the mutant fruit fly gigas, originally described in 1976 by Drs. Ferrus and Garcia-Bellido, contained a mutation in the human homolog for tuberin (Fig. 1). The loss of tuberin resulted in a defect in cell cycle control, which caused the cells to repeat S phase without entering M phase. The mechanism of growth inhibition was elucidated in 2001 by three Drosophila laboratories which reported that tuberin and hamartin are key members of the PI3K/PKB(Akt)/S6K signaling pathway that regulates cellular size. The precise positioning of tuberin in the Akt/S6K pathway was accomplished by elegant genetic analyses from three Drosophila laboratories (Fig. 2). These studies demonstrated that tuberin and hamartin associate into a complex that functions as a master regulator for the kinase mTOR, or mammalian target of rapamycin, through an intermediate G protein called Rheb. The intact tuberin/hamartin complex maintains Rheb in an inactivated, phospholylated state. Phosphorylation of tuberin by Akt dissociates the tuberin/hamartin complex, shifts the Rheb-GTP/Rheb GDP balance in favor of Rheb-GTP, and permits activation of downstream targets through mTOR to S6K and the initiation factor 4E binding protein (4E-BP1), which initiate protein synthesis and cell growth. Genetic mutations that result in the absence or dysfunction of tuberin or hamartin, as occur in patients with tuberous sclerosis and LAM, cause constitutive activation of S6K and 4E-BP1. Data from experimental animals and humans confirms the relevance of the Akt signaling pathways in tuberous sclerosis in vivo. Although not perfect mimics of the human disease, tuberin and hamartin heterozygous null mice develop several neoplastic lesions which are felt to be potential models for tuberous sclerosis, including renal and hepatic tumors. The hepatic tumors are rich in smooth muscle and are HMB-45 positive, consistent with the histological and immunohistochemical characteristics of LAM and AML lesions from human patients. Female mice die disproportionately from fatal hemorrhage into the liver lesion after one year of age, suggesting an influence of estrogen that also mimics human LAM. Most encouraging is that S6K is constitutively activated in the lesions of the TSC1+/- mice, and rapamycin quenches both the S6K phosphorylation and inappropriate cell growth in murine embryonic fibroblasts isolated from the animals. Preliminary data presented at the Tuberous Sclerosis Research Conference in Chantilly, Virginia, demonstrated that rapamycin causes shrinkage of renal tumors in mouse and rat TSC models, associated with inhibition of S6K phosphorylation and abundant apoptosis. Goncharova and Krymskaya demonstrated abundant S6K phosphorylation and unregulated cell growth in LAM cells isolated from patients that had undergone lung transplant. They further demonstrated rapamycin, which binds and inactivates downstream targets in the Akt pathway, mTOR, could mimic the function of the tuberin/hamartin complex and restore orderly cell growth. These studies form the basis for the trial of rapamycin in patients with tuberous sclerosis and LAM, currently underway in the United States and Europe.

Fig. 2. Model for how tuberin and hamartin regulate cell growth

Binding of ligands (such as insulin) to cell surface tyrosine kinase receptors results in autophosphorylation of the receptor, and docking of adaptor proteins and PI3 kinase (PI3K). Protein kinase B (PKB), also known as Akt, is phosphorylated and activated, which in turn phosphorylates tuberin. Tuberin dissociates from hamartin, shifting the Rheb-GDP/GTP balance in favor of Rheb-GTP and permitting phosphorylation and activation of mTOR. Activated mTOR phosphorylates S6K and initiation factor 4E binding protein (4E-BP1), which together initiated protein synthesis and cell growth. Absence of tuberin permits constitutive activation of S6K and 4E-BP1, which provides a persistent and inappropriate stimulus for growth.

We have been encouraged by preliminary evidence from the Cincinnati Angiomyolipoma Sirolimus Trial that lung function can be favorably affected by sirolimus. The structure of the Sirolimus Multicenter International Lymphangioleiomyomatosis Efficacy and Safety (SMILES) Trial will be provided by the Rare Lung Disease Consortium. A total of 240 patients will be randomized to receive sirolimus or placebo over a two-year period, and lung function will be followed during serial clinic visits. The primary endpoint is the FEV1 response at 24 months. A short description of the trial is included in the appendix.

There are many questions left unanswered. Where do the estrogen and Akt signaling pathways intersect? Why do only a fraction of women with tuberous sclerosis develop LAM? What are the modifier genes that influence the expression and severity of LAM in patients? Why does the melanoma specific HMB-45 epitope, the pigment pathway protein gp100, consistently appear in LAM lesions? How does loss of tuberin function result in the elaboration of matrix degrading enzymes? What is the origin of the smooth muscle cells that infiltrate the lung in LAM? If LAM proves to be a metastatic disease due to migration of cells to the lung, what is the source and what are the roles of estrogen and growth factors in adhesion molecule expression, metastasis, implantation, infiltration and proliferation of LAM cells? We are confident that the 2005 LAM Conference will provide an ideal forum for the exchange of data and the integration of new concepts, and a mechanism to focus the efforts of the scientific community.

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