Lymphangioleiomyomatosis (LAM)

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Lymphangioleiomyomatosis (LAM)

Postby patoco » Sat Jun 10, 2006 11:37 pm

Lymphangioleiomyomatosis (LAM)

Our Home Page: Lymphedema People

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What is Lymphangioleiomyomatosis?

Lymphangioleiomyomatosis (LAM) is a rare lung disease that was first described in the medical literature by von Stossel in 1937. The disease is characterized by an unusual type of muscle cell that invades the tissue of the lungs, including the airways, and blood and lymph vessels. Over time, these muscle cells form into bundles and grow into the walls of the airways, and blood and lymph vessels, causing them to become obstructed.

Although these cells are not considered cancerous, they act somewhat like cancer cells in that they grow uncontrollably throughout the lung. Over time, the muscle cells block the flow of air, blood, and lymph to and from the lungs, preventing the lungs from providing oxygen to the rest of the body.

Kidney tumors that are often asymptomatic may also be found in patients with LAM.

Lymphangioleiomyomatosis is pronounced lim - fan'- je - o - Li'- o - mi'- o - ma - to'- sis. Lymph and angio refer to the lymph and blood vessels. Leiomyomatosis refers to the formation of the bundles of the unusual muscle cells.

The cause of LAM is not known. However, a recent paper reports that tuberous sclerosis gene mutations are a cause of lymphyangioleiomyomatosis (LAM). The mutations were found in the angiomyolipoma cells and LAM cells from four women with LAM. The mutations were not present in normal lung, kidney or blood cells, indicating that these women with LAM do not have the inherited disease, tuberous sclerosis. Identifying this genetic link between tuberous sclerosis and sporadic LAM is an important step in LAM research. [Ref: Mutations in the tubersous sclerosis complex gene TSC2 are a cause of sporatic lymphyangioleiomyomatosis; Carsillo, Astrinidis and Henske; PNAS 2000 97:6085-90.]

How Common is LAM?

LAM affects almost exclusively women of childbearing age, although several cases have been reported in which the disease was thought to have developed after menopause. The international literature also includes reports of a few cases in men.

The precise number of people who have LAM is not known. It has been estimated that there may be up to several hundred women in the United States with the disease.

It also has been suggested that LAM has become more common during the past 5 to 10 years, although it may be that doctors are doing a better job of diagnosing it.

What are the symptoms of LAM?

A common symptom of LAM is shortness of breath (dyspnea) with physical activity. In the early stages of disease, the person with LAM may experience shortness of breath only during strenuous exercise, but as the disease advances, there may be shortness of breath even at rest. Another common symptom is chest pain, and occasionally patients cough up small amounts of blood.

The symptoms associated with LAM are caused by the excessive growth of the muscle cells around the airways, and blood and lymph vessels. The excess muscle cells can block the airways, trapping air in the smallest air compartments in the lung (alveoli) and causing the person with LAM to have difficulty moving air out of the lungs. This results in a breakdown of the lung tissue and the formation of small cysts (air filled cavities).
Cysts near or on the surface of the lung (blebs) can rupture and, as air leaks from the lung into the chest cavity (pneumothorax), the lung or a part of the lung can collapse, causing pain. If the amount of air that leaks out is small, the lung may seal over the space and re-expand itself. If air continues to leak into the chest cavity, however, it may be necessary to re-expand the collapsed portion of the lung by removing the air that has leaked into the chest cavity. This is an inpatient procedure, done using a tube inserted through the chest wall into the chest cavity.

The excessive muscle growth may also block blood vessels in the lung, causing them to become distended with blood and even to rupture. This can result in the patient coughing up blood-stained sputum or blood (hemoptysis).

Obstruction of the lymphatic vessels by the excess muscle growth can lead to leakage of fluid into the chest cavity (pleural effusion). The fluid may be straw-colored (lymph), or fat-containing, milky white (chyle), or pinkish-red if it contains blood. A physician can remove some of this fluid with a needle and syringe to deteremine its composition and origin. If large amounts of this fluid accumulate in the chest cavity, it may have to be removed through a tube surgically inserted into the chest.

It is estimated that 30 to 50 percent of LAM patients will develop leakage of air into the chest cavity (pneumothorax), and up to 80 percent will have leakage of fluid into the chest cavity (pleural effusions). Coughing up blood-stained sputum or blood (hemoptysis) occurs less frequently.

What is the course of LAM?

LAM is generally progressive, leading to increasingly impaired lung function. The rate of development can vary considerably among patients.
As the disease advances, there is more extensive growth of muscle cells throughout the lung and repeated leakage of fluid into the chest cavity (pleural effusions). As an increasing number of cysts are formed, the lung takes on a honeycomb appearance.

The survival time following the diagnosis of LAM is uncertain, as the disease seems to be highly individual. It had been reported to be less than 10 years, but new reports show patients living more than 20 years after diagnosis.

How is LAM Diagnosed?

The diagnosis of LAM can be difficult because many of the early symptoms are similar to those of other lung diseases, such as asthma, emphysema, or bronchitis. Often the person with LAM first goes to the physician complaining of chest pain and shortness of breath that was caused by a pneumothorax.

Some patients first consult their physician because of shortness of breath upon exertion or a collapsed lung.

There are a number of tests the physician can do to confirm or rule out the existence of LAM.

Chest X-ray

·This is a simple procedure that provides a picture of the lungs and other tissue in the chest. The chest x-ray is used to diagnose a pneumothorax or the presence of fluid in the chest cavity (pleural effusion). Smooth muscle cysts, consistent with LAM, do not usually appear on an x-ray.

Pulmonary Function Tests

·The patient breathes through a mouthpiece into a machine (spirometer) that measures the volume of air in the lungs, the movement of air into and out of the lungs, and the movement of oxygen from the lungs into the blood.

Blood Tests

·The patient's blood is analyzed to determine whether the lungs are providing an adequate supply of oxygen to the blood.

Computed Tomography (CT)

·Computed tomography (CT) is the most definitive imaging test for diagnosing LAM.

·The patient lies inside a long, cylindrical structure, and x-ray beams pass through the body from different angles, producing multiple images. A computer combines all of these images and provides a 3-dimensional picture of the inside of the lungs and chest. This is called a CT scan.

·On a CT scan, the presence of thin-walled cysts spread relatively uniformly throughout the lungs usually means LAM.

·A CT scan should also be done of the abdominal area, as there is a benign kidney tumor called angiomyolipoma that is associated with LAM.

Lung Biopsy

·Two or more of the manifestations listed above (cysts, fluid in the lungs, benign kidney tumor, and collapsed lung) can give a clear diagnostic of LAM. An open lung biopsy should be performed as a last resort to diagnose LAM. In this procedure, a few small pieces of lung tissue are removed through an incision made in the chest wall between the ribs.

·Another procedure, thoracoscopy, is also being used in some patients to obtain lung tissue. In this procedure, tiny incisions are made in the chest wall, and a small lighted tube (endoscope) is inserted so that the interior of the lung can be viewed, and small pieces of tissue are removed.

·Both procedures must be done in the hospital under general anesthesia. Another technique, called transbronchial biopsy, may also be used to obtain a small amount of lung tissue. A long, narrow, flexible, lighted tube (bronchoscope) is inserted down the windpipe (trachea), and into the lungs. Bits of lung tissue are sampled, using a tiny forceps. This procedure is usually done in a hospital on an outpatient basis under local anesthesia. It is less reliable than an open lung biopsy because the amount of tissue that can be sampled is sometimes inadequate for diagnostic studies.

·After the lung tissue is removed, it is examined in a pathology laboratory for the presence of the abnormal muscle cells and cystic changes characteristic of LAM.

How is LAM Treated?

Because LAM affects almost exclusively women of childbearing age, physicians have thought that the hormone estrogen might be involved in the abnormal muscle cell growth that characterizes the disease, just as it is in the growth of smooth muscle in the uterus in a woman's childbearing years.

Although there is no evidence that there is a relationship between estrogen and LAM, the treatment of LAM has focused on reducing the production or effects of estrogen. The response to treatment has been highly individual, and no therapy has been found to be effective for all LAM patients.

Oxygen therapy may be necessary if the disease continues to worsen and lung function is impaired.

For LAM patients with severe disease, lung transplantation is an established therapy. One year survival following transplant is approximately 70 percent, and 3-year survival is approximately 50 percent.

What is the Effect of LAM on the Patient's Lifestyle?

In the early stages of the disease, most patients can go about their daily activities, including attending school, going to work, and performing common physical activities, such as walking up a hill. In more advanced stages, the patient may have very limited ability to move around and may require oxygen full-time.

Patients with LAM should follow the same healthy lifestyle recommended for the general population, including eating a healthy diet, getting as much exercise as they can, as well as plenty of rest, and, of course, not smoking. Traveling to remote areas where medical attention is not readily available or to high altitudes where the blebs can expand and rupture should be considered carefully before undertaken.

In patients with normal lung function, there is probably no increased risk associated with pregnancy. However, in patients with compromised lung function, pregnancy is not advised.

There do not appear to be complications associated with oral contraceptives, but this issue should be discussed with the patient's pulmonologist and gynecologist.

To learn more about this disease visit the LAM Foundation. For those who suffer from this disease there is also an email support group that you can join.

http://www.lung.ca/diseases-maladies/a- ... ndex_e.php

Related Article:

Sleep desaturation and its relationship to lung function, exercise and quality of life in LAM.
Mar 2012

Keywords: Lymphangioleio myomatosis (LAM), Polysomnography, Sleep hypoxaemia, Six-minute walk test, Lung function test

http://www.resmedjournal.com/article/S0954-6111(11)00474-4/abstract

Menstrual cycle variation of retroperitoneal lymphangioleiomyomas in lymphangioleiomyomatosis.
Dec 2011

Keywords: lymphangioleiomyomatosis;abdominal lymphangioleiomyoma;female not allowed hormones

http://onlinelibrary.wiley.com/doi/10.1 ... x/abstract

Lymphangioleiomyomatosis

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Lymphangioleiomyomatosis

Wrong Diagnosis

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Lymphangioleiomyomatosis in the medical literature

Postby patoco » Sat Jul 14, 2007 8:12 am

Genetic and Morphologic Determinants of Pneumothorax in Lymphangioleiomyomatosis.

Am J Physiol Lung Cell Mol Physiol. 2007 Jul

Steagall WK, Glasgow CG, Hathaway OM, Avila NA, Taveira-Dasilva AM, Rabel A, Stylianou MP, Lin JP, Chen X, Moss J.
PCCMB, NHLBI, NIH, Bethesda, Maryland, United States.

* To whom correspondence should be addressed. E-mail: mossj@nhlbi.nih.gov.

Lymphangioleiomyomatosis, a multisystem disease affecting women, is
characterized by proliferation of abnormal smooth muscle-like cells in the lungs, leading to cystic destruction of the parenchyma and recurrent pneumothoraces. Clinical characteristics of lymphangioleiomyomatosis patients were analyzed to determine the relationship of pneumothoraces to disease progression. Patients were genotyped for polymorphisms in genes of extracellular matrix proteins collagen, elastin, and matrix metalloproteinase-1 to assess their association with pneumothoraces.

Clinical data and polymorphisms in the genes for Types I and III collagen, elastin, and matrix metalloproteinase-1 were compared with the prevalence of pneumothorax. Of 227 patients, 57% reported having had at least one pneumothorax. Cyst size on high resolution computed tomography scans was associated with pneumothorax; patients with a history of pneumothorax were more likely to have larger cysts than patients who had no pneumothoraces. In patients with mild disease, those with a history of pneumothorax had a faster rate of decline in FEV1 (P=0.001, adjusted for age) than those without.

Genotype frequencies differed between patients with and without pneumothorax for polymorphisms in the Types I and III collagen and matrix metalloproteinase-1 genes. Larger cysts may predispose lymphangioleiomyomatosis patients to pneumothorax, which, in early stages of disease, correlates with a more rapid rate of decline in FEV1. Polymorphisms in Types I and III collagen and matrix metalloproteinase-1 genes may cause differences in lung extracellular matrix that result in greater susceptibility to pneumothorax.

Key words: cystic lung disease, collagen, matrix metalloproteinases, elastin.

Full Text Article

http://ajplung.physiology.org/cgi/conte ... 176.2007v1

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Lymphangioleiomyomatosis (LAM)--an uncommon cause of bilateral spontaneous pneumothorax

Rev Med Chir Soc Med Nat Iasi. 2007 Jan-Mar

Grigorescu C, Bosânceanu M, Boişteanu D, Aldea A, Chiseliţă I, Cozma LG.
Clinica de Chirurgie Toracică, Facultatea de Medicină, Universitatea de Medicină si Farmacie "Gr. T. Popa", Iaşi.

LAM, a rare lung disease typically affecting women of reproductive age, is characterized by abnormal proliferation of smooth--muscle cells and progressive loss of pulmonary function due to destruction of lung parenchyma. Two cases of bilateral succesive recurrent spontaneous pneumothorax and haemoptysis are presented. Repeated conventional and video-assisted surgery was required in both cases, for drainage of the recurrent pneumothorax and resection of subpleural bulae, with good immediate postoperative evolution. Immunohistochemical studies of resected specimens revealed LAM cells in the lung parenchyma with receptors for oestrogen and progesterone. HMB45 monoclonal antibodies in the LAM cells were identified in one case. The follow-up of the patients revealed no signs of recurrence at 84 and 18 months respectively, although pulmonary transplantation should be considered in case of further deterioration of respiratory function.

PMID: 17595857 [PubMed - in process]

http://www.ncbi.nlm.nih.gov/sites/entre ... d_RVDocSum

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Primary retroperitoneal lymphangioleiomyomatosis in a postmenopausal woman: a case report and review of the literature

Int J Gynecol Cancer. 2007 Mar-Apr

Kebria M, Black D, Borelli C, Modica I, Hensley M, Chi DS.
Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.

Dennis S. Chi, MD, Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, MRI-1026, New York, NY 10021, USA. Email: gynbreast@mskcc.org
M. Kebria is presently at Department of Obstetrics and Gynecology, The Cleveland Clinic Foundation, Cleveland, Ohio.

Kebria M, Black D, Borelli C, Modica I, Hensley M, Chi DS. Primary retroperitoneal lymphangioleiomyomatosis in a postmenopausal woman: a case report and review of the literature. Int J Gynecol Cancer 2007;17:528–532.

Keywords: extrapulmonary lymphangioleiomyomatosis,
smooth muscle proliferation, tuberous sclerosis

Lymphangioleiomyomatosis (LAM) is a rare progressive disease of unknown etiology that typically affects women of childbearing age. It is characterized by an abnormal proliferation of smooth muscle cells causing gradual obstruction of small airways, frequently resulting in respiratory failure and death. While LAM is predominantly a lung disorder, we report a case of retroperitoneal LAM in a patient who had no evidence of pulmonary involvement. A 59-year-old female presented with postmenopausal bleeding and no other complaints. She was found to have a low attenuation retroperitoneal mass on abdominal and pelvic computed tomography (CT) scan suspicious for lymphoma. CT-guided biopsy was nondiagnostic. Laparoscopic resection of some of the enlarged retroperitoneal lymph nodes confirmed the diagnosis of LAM. This case is an atypical presentation of LAM. The disease typically presents in premenopausal women, with the initial site of involvement being the lungs and mediastinum. In rare cases, such as this of extrapulmonary LAM, patients typically present with a palpable abdominal mass, abdominal pain, or chylous ascites. As in our case, radiographic findings can mimic malignancies such as lymphoma. Laparoscopic lymph node biopsy is a valuable tool in these situations of diagnostic dilemma.

http://www.blackwell-synergy.com/doi/ab ... 07.00785.x

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A case of lymphangioleiomyomatosis found due to chylous ascites, pleural effusion and pelvic lymphadenopathy

Nihon Kokyuki Gakkai Zasshi. 2007 May

Yano T, Hasizume I, Kasamatsu N, Kato T, Shibata M, Ashinuma N, Kobayashi K, Yasuda T, Nakamura A.
Department of Respiratory Medicine, Hamamatsu Medical Center.

We report a case of lymphangioleiomyomatosis, complaining initially of abdominal distension due to massive chylous ascites. The patient was a 28-year-old woman in whom abdominal ultrasound had strongly suggested the existence of both pelvic lymphadenopathy and massive ascites, the latter subsequently turning out to be chylous. Pelvic lymph node biopsy yielded a diagnosis of lymphangioleiomyomatosis. High-resolution computed tomography (HRCT) of the chest showed no remarkable findings except for very few cystic changes in the lung parenchyma. Pulmonary function had remained normal except for a temporary constrictive pattern when chylous pleural effusion developed. No airflow obstruction was detected on pulmonary function tests. Although lymphangioleiomyomatosis is often associated with pulmonary symptoms, we should bear in mind the possibility of lymphangioleiomyomatosis even in the absence of such symptoms when facing any woman of child-bearing age with abdominal chylous ascites of unknown etiology.

PMID: 17554983 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/sites/entre ... d_RVDocSum

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Pulmonary lymphangioleiomyomatosis (LAM): Progress and current challenges

J Cell Biochem. 2007 May 31

Goncharova EA, Krymskaya VP.
Department of Medicine, University of Pennsylvania, Pennsylvania.

email: Vera P. Krymskaya (krymskay@mail.med.upenn.edu)

*Correspondence to Vera P. Krymskaya, Translational Research Laboratories, Suite 1200, Room 1212, 125 South 31st Street, Philadelphia, PA 19104-3403.

Funded by:
NIH/NHLBI; Grant Number: 2RO1HL071106
American Lung Association; Grant Number: CI-9813
The LAM Foundation; Grant Number: LAM048F01-05 and LAM059P07-06

Keywords:
TSC1 • TSC2 • smooth muscle • lung • tumor • signal transduction

Lymphangioleiomyomatosis (LAM), a rare lung disease, is characterized by the progressive proliferation, migration, and differentiation of smooth muscle (SM)-like LAM cells, which lead to the cystic destruction of the lung parenchyma, obstruction of airways and lymphatics, and loss of pulmonary function.

LAM is a disease predominantly affecting women and is exacerbated by pregnancy; only a lung transplant can save the life of a patient. It has been discovered that in LAM, somatic or genetic mutations of tumor suppressor genes tuberous sclerosis complex 1 (TSC1) or TSC2 occur and the TSC1/TSC2 protein complex functions as a negative regulator of the mTOR/S6K1 signaling pathway. These two pivotal observations paved the way for the first rapamycin clinical trial for LAM.

The recent discoveries that TSC1/TSC2 complex functions as an integrator of signaling networks regulated by growth factors, insulin, nutrients, and energy heightened the interest regarding this rare disease because the elucidation of disease-relevant mechanisms of LAM will promote a better understanding of other metabolic diseases such as diabetes, cancer, and cardiovascular diseases. In this review, we will summarize the progress made in our understanding of TSC1/TSC2 cellular signaling and the molecular mechanisms of LAM; we will also highlight some of the lesser explored directions and challenges in LAM research. J. Cell. Biochem.

http://www3.interscience.wiley.com/cgi- ... 1&SRETRY=0

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Pulmonary Lymphangioleiomyomatosis in a Karyotypically Normal Man without Tuberous Sclerosis Complex

Am J Respir Crit Care Med. 2007 Jul

Schiavina M, Di Scioscio V, Contini P, Cavazza A, Fabiani A, Barberis M, Bini A, Altimari A, Cooke RM, Grigioni WF, D'Errico-Grigioni A.
Istituto di Oncologia F. Addarii, Viale Ercolani 4/2, 40138 Bologna, Italy. derrico@aosp.bo.it.

Key Words: smooth muscle cells • histopathology • not allowed distribution • rare diseases

Rationale: The three previously reported cases of conclusively documented pulmonary lymphangioleiomyomatosis (LAM) in men were associated with definite or probable tuberous sclerosis complex (TSC).

OBJECTIVES: To describe an unequivocal case of pulmonary LAM occurring in a man with no clinical or genotypic evidence of TSC.

Methods: At high-resolution computed tomography, a 37-year-old phenotypically and karyotypically normal man with left pneumothorax and massive pulmonary collapse had widespread thin-walled cysts throughout both lungs. Histological diagnosis of LAM was performed on biopsy material, and immunohistochemically confirmed with the HMB-45 monoclonal antibody.

Measurements and Main Results: Remarkably, the HMB-45-positive cells lining the cysts also showed strong reactivity for estrogen and progesterone receptor proteins. TSC was clinically excluded, and TSC1 and TSC2 germline mutations were not detected at DNA analysis.

Conclusions: This article indicates that occurrence of LAM may be possible in a chromosomally normal man unaffected by TSC. On diagnostic grounds, the possibility of LAM should be borne in mind when diffuse cystic lung disease occurs in a man, even in the absence of signs of TSC.

http://ajrccm.atsjournals.org/cgi/conte ... t/176/1/96

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D2-40 labeling in lymphangiomyoma/lymphangiomyomatosis of the soft tissue: further evidence of lymphangiogenic tumor histogenesis

Virchows Arch. 2007 Apr

Hansen T, Katenkamp K, Bittinger F, Kirkpatrick CJ, Katenkamp D.
Institute of Pathology, Johannes Gutenberg University of Mainz, Langenbeckstr. 1, 55101, Mainz, Germany. hansen@pathologie.klinik.uni-mainz.de

Keywords: Lymphangio(leio)myoma - Lymphangio(leio)myomatosis - Podoplanin - D2-40 - Lymphatic tumor vessels

We examined ten cases of extrapulmonary lymphangioleiomyoma/lymphangioleiomyomatosis (LAM; all patients female; median age 46.5 years) for immunohistochemical labeling with a monoclonal antibody against podoplanin (D2-40), which is specific for lymphatic endothelial lining. We found positive staining in thin-wall branching vessels reflecting the lymphatic nature of tumor vessels in all cases tested. In contrast, perivascular (HMB-45 positive) myoid cells were not detected by D2-40. The D2-40 labeling confirms the current concept of lymphangiogenic origin of the tumor vessels in LAM. In addition, this study makes a further contribution to the immunohistochemical mapping of this antibody in vascular tumors. Finally, the use of this commercially available antibody provides an additional help in the differential diagnosis of LAM from other soft tissue tumors.

http://www.springerlink.com/content/j6124390873016n2/

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Pulmonary lymphangioleiomyomatosis

Saudi Med J. 2007 Jan

Shawki HB, Muhammed SM, Reda AN, Abdulla TS, Ardalan DM.
Department of Medicine, Faculty of Medicine, Baghdad University, PO Box 10396, Iraq. hilal@iraqi-cts.org

A 38-year-old Iraqi female, presented with one-year history of exertional dyspnea and exercise intolerance, without systemic or constitutional symptoms. Clinical examination revealed bilateral basal crackles with signs suggestive of left side pleural effusion, chest x-ray showed left sided pleural effusion, and diffuse bilateral basal pulmonary shadowing. Her biochemical analysis, hematological tests, electrocardiogram and echocardiography were normal, aspiration of the fluid revealed a chylothorax, the radiological shadowing was proved by computed tomography scan of the chest to be diffuse cystic lesions involving mostly the lower lobes. Open lung biopsy showed dilated lymphatic vessels with surrounding inflammatory cells and smooth muscle fibers consistently with the diagnosis of pulmonary lymphangioleiomyomatosis LAM.

PMID: 17206306 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/sites/entre ... d_RVDocSum

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Sporadic lymphangioleiomyomatosis and tuberous sclerosis complex with lymphangioleiomyomatosis: comparison of CT features


Radiology. 2007 Jan

Avila NA, Dwyer AJ, Rabel A, Moss J.
Diagnostic Radiology Department, Warren G. Magnuson Clinical Center, and Pulmonary-Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1182, USA. navila@nih.gov

PURPOSE: To retrospectively compare the frequencies of computed tomographic (CT) findings in patients with lymphangioleiomyomatosis (LAM) and patients with tuberous sclerosis complex (TSC) and LAM.

MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained for the HIPAA-compliant study. In 256 patients with LAM (mean age, 44 years) and 67 patients with TSC/LAM (mean age, 40 years), CT scans of the chest, abdomen, and pelvis were reviewed by a single radiologist. The fraction of lung involvement with cysts was estimated from high-spatial-resolution CT scans. Other findings assessed included noncalcified pulmonary nodules, pleural effusion, thoracic duct dilatation, hepatic and renal angiomyolipomas (AMLs), lymphangioleiomyoma (LALM), ascites, nephrectomy, and renal embolization. Confidence intervals and hypothesis tests of differences in frequencies, comparison of age quartiles, RIDIT analysis, analysis of variance, and correlation coefficients were used in the statistical analysis.

RESULTS: Patients with LAM had more extensive lung involvement (RIDIT score, 0.36) and higher frequency of LALM (29% vs 9%, P<.001), thoracic duct dilatation (4% vs 0, P=.3), pleural effusion (12% vs 6%, P=.2), or ascites (10% vs 6%, P=.3). Patients with TSC/LAM had higher frequency of noncalcified pulmonary nodules (12% vs 1%, P<.01), hepatic (33% vs 2%, P<.001) and renal (93% vs 32%, P<.001) AMLs, nephrectomy (25% vs 7%, P<.001), or renal artery embolization (9% vs 2%, P<.05).

CONCLUSION: The extent of lung disease is greater in LAM than TSC/LAM. Hepatic and renal AMLs and noncalcified lung nodules are more common in TSC/LAM, while lymphatic involvement-thoracic duct dilatation, chylous pleural effusion, ascites, and LALM-is more common in LAM. Copyright (c) RSNA, 2006.

http://radiology.rsnajnls.org/cgi/conte ... /242/1/277

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Molecular pathogenesis of lymphangioleiomyomatosis: lessons learned from orphans

Am J Respir Cell Mol Biol. 2007 Apr

Juvet SC, McCormack FX, Kwiatkowski DJ, Downey GP.
National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206, USA.

Correspondence and requests for reprints should be addressed to Gregory P. Downey, M.D., Executive Vice President Academic Affairs, K701b, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206. E-mail: downeyg@njc.org

Key Words: tuberous sclerosis • TSC1 • TSC2 • mTOR • signal transduction • estrogen

Lymphangioleiomyomatosis (LAM) is a rare progressive cystic lung disease affecting young women. The pivotal observation that LAM occurs both spontaneously and as part of the tuberous sclerosis complex (TSC) led to the hypothesis that these disorders share common genetic and pathogenetic mechanisms. In this review we describe the evolution of our understanding of the molecular and cellular basis of LAM and TSC, beginning with the discovery of the TSC1 and TSC2 genes and the demonstration of their involvement in sporadic (non-TSC) LAM. This was followed by rapid delineation of the signaling pathways in Drosophila melanogaster with confirmation in mice and humans. This knowledge served as the foundation for novel therapeutic approaches that are currently being used in human clinical trials.

http://ajrcmb.atsjournals.org/cgi/conte ... t/36/4/398
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Sirolimus for Angiomyolipoma in Lymphangioleiomyomatosis

Postby patoco » Thu Jan 10, 2008 12:29 am

Sirolimus for Angiomyolipoma in Tuberous Sclerosis Complex or Lymphangioleiomyomatosis

January 10, 2008

John J. Bissler, M.D., Francis X. McCormack, M.D., Lisa R. Young, M.D., Jean M. Elwing, M.D., Gail Chuck, L.M.T., Jennifer M. Leonard, R.N., Vincent J. Schmithorst, Ph.D., Tal Laor, M.D., Alan S. Brody, M.D., Judy Bean, Ph.D., Shelia Salisbury, M.S., and David N. Franz, M.D.

ABSTRACT

Background: Angiomyolipomas in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis are associated with mutations in tuberous sclerosis genes resulting in constitutive activation of the mammalian target of rapamycin (mTOR). The drug sirolimus suppresses mTOR signaling.

Methods: We conducted a 24-month, nonrandomized, open-label trial to determine whether sirolimus reduces the angiomyolipoma volume in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. Sirolimus was administered for the first 12 months only. Serial magnetic resonance imaging of angiomyolipomas and brain lesions, computed tomography of lung cysts, and pulmonary-function tests were performed.

Results: Of the 25 patients enrolled, 20 completed the 12-month evaluation, and 18 completed the 24-month evaluation. The mean (±SD) angiomyolipoma volume at 12 months was 53.2±26.6% of the baseline value (P<0.001) and at 24 months was 85.9±28.5% of the baseline value (P=0.005). At 24 months, five patients had a persistent reduction in the angiomyolipoma volume of 30% or more. During the period of sirolimus therapy, among patients with lymphangioleiomyomatosis, the mean forced expiratory volume in 1 second (FEV1) increased by 118±330 ml (P=0.06), the forced vital capacity (FVC) increased by 390±570 ml (P<0.001), and the residual volume decreased by 439±493 ml (P=0.02), as compared with baseline values. One year after sirolimus was discontinued, the FEV1 was 62±411 ml above the baseline value, the FVC was 346±712 ml above the baseline value, and the residual volume was 333±570 ml below the baseline value; cerebral lesions were unchanged. Five patients had six serious adverse events while receiving sirolimus, including diarrhea, pyelonephritis, stomatitis, and respiratory infections.

Conclusions Angiomyolipomas regressed somewhat during sirolimus therapy but tended to increase in volume after the therapy was stopped. Some patients with lymphangioleiomyomatosis had improvement in spirometric measurements and gas trapping that persisted after treatment. Suppression of mTOR signaling might constitute an ameliorative treatment in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. (ClinicalTrials.gov number, NCT00457808 [ClinicalTrials.gov] .)

Source Information

From the Divisions of Nephrology and Hypertension (J.J.B.), Pulmonary Medicine (L.R.Y.), Neurology (G.C., J.M.L., D.N.F.), Radiology (V.J.S., T.L., A.S.B.), and Biostatistics (J.B., S.S.), Cincinnati Children's Hospital Medical Center; and the Division of Pulmonary and Critical Care, University of Cincinnati College of Medicine (F.X.M., L.R.Y., J.M.E.) — both in Cincinnati.

Drs. McCormack, Young, and Franz contributed equally to the article.

Address reprint requests to Dr. Bissler at Cincinnati Children's Hospital Medical Center, MLC 7022, 3333 Burnet Ave., Cincinnati, OH 45229-3039, or at john.bissler@cchmc.org.

http://content.nejm.org/cgi/content/sho ... ?query=TOC

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Pat O'Connor
Lymphedema People
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Re: Lymphangioleiomyomatosis (LAM)

Postby patoco » Mon Jul 06, 2009 9:56 am

Lymphangioleiomyomatosis: a case report

J Womens Health (Larchmt). 2009 Apr

Borovansky JA, Labonte HR, Boroff ES, Ruddy BE, Mayer AP.
Division of Community Internal Medicine, Mayo Clinic, Scottsdale, Arizona 85259, USA. borovansky.jill@mayo.edu

Lymphangioleiomyomatosis (LAM) is a rare disease of unknown cause that traditionally affects young women of reproductive age. It is characterized by a proliferation of atypical smooth muscle cells, preferentially along the bronchovascular structures, that causes progressive respiratory failure. LAM is almost universally fatal without a lung transplant, although new clinical trials are ongoing. Because of its rareness and nonspecific presenting symptoms, patients often receive a missed or delayed diagnosis. We present the case of a 51-year-old postmenopausal woman who had hemoptysis ultimately determined to be due to LAM. As is common for patients with LAM, the initial chest radiograph was unremarkable, whereas subsequent computed tomography (CT) demonstrated the distinctive pulmonary parenchymal cysts. Biopsy of an HMB-45-positive, para-aortic lymphangiomyoma provided further confirmation of the diagnosis. LAM may be more common than previously recognized, and it is imperative for primary care providers to be able to recognize this disease so they can make prompt referrals to appropriate specialty centers.

Mary Ann Liebert Publications - Full Text Article at Link Below

http://www.liebertonline.com/doi/abs/10 ... .2008.0967

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Lung transplantation for lymphangioleiomyomatosis: the European experience.

J Heart Lung Transplant. 2009 Jan

Benden C, Rea F, Behr J, Corris PA, Reynaud-Gaubert M, Stern M, Speich R, Boehler A.
Division of Pulmonary Medicine, University Hospital Zurich, Zurich, Switzerland.

BACKGROUND: Lung transplantation has been accepted widely as therapy for end-stage pulmonary lymphangioleiomyomatosis (LAM); however, single-center and national experience is limited due to the rarity of LAM. METHODS: We report the recent European experience of lung transplantation for LAM. A self-administered questionnaire was distributed to 30 European lung transplant centers to evaluate patients who underwent primary lung transplantation for LAM (1997 to 2007). RESULTS: Seventy percent of centers responded to the questionnaire. A total of 61 lung transplants were undertaken in women only, with mean age at transplant 41.3 years (SD 5.1). Centers performed a median of 2 (0 to 9) transplant operations. Severe pleural adhesions were the most common intra-operative complication. Early deaths (N = 6) were due to primary graft or multiple-organ failure or sepsis. Twelve recipients were diagnosed with bronchiolitis obliterans syndrome at a median of 20 months (range 10 to 86 months) post-transplant. LAM-related complications included renal angiomyolipoma and pneumothorax in the native lung. Recurrence of LAM occurred in 4 recipients. As of December 2007, actuarial Kaplan-Meier survival was 79% at 1 year and 73% at 3 years post-transplant. CONCLUSIONS: Post-transplant outcome for pulmonary LAM in the recent era appears to have improved compared with the previous era. LAM-related complications remain common, but recurrence of LAM in the allograft is rare.

Elsevier - Science Direct

http://www.sciencedirect.com/science?_o ... 3b14574535

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Pregnancy experiences among women with lymphangioleiomyomatosis.

Respir Med. 2009 May

Cohen MM, Freyer AM, Johnson SR.
Women's Health Research Institute, Women's College Hospital, Toronto, Ontario, Canada. marsha.cohen@sympatico.ca

Lymphangioleiomyomatosis (LAM) is a rare lung disease affecting women. Following case reports that pregnancy exacerbates LAM, patients are frequently advised to avoid pregnancy. Our objective was to determine pregnancy and health outcomes in LAM to provide better evidence with which to council patients contemplating pregnancy. We surveyed 328 women with LAM regarding pregnancy outcomes, pulmonary function, subjective and psychological functioning, quality of life, dyspnoea and fatigue. Amongst childless women the main reason not to attempt pregnancy was based on concerns about potential effects of pregnancy on LAM. Almost two thirds of patients had been pregnant, the majority before LAM was diagnosed, in whom pregnancy outcome was generally favourable. Women diagnosed with LAM (n=15) during pregnancy had high rates of pneumothorax (67%), miscarriage (7%) and premature birth (47%). The group diagnosed with LAM before or during pregnancy (n=12) had lower mean FEV(1), FVC and DLCO after pregnancy compared with those diagnosed following pregnancy or never pregnant. There were no differences in subjective or psychological functioning, quality of life, dyspnoea or fatigue scores between groups. In newly diagnosed LAM patients there was a high incidence of premature birth and pneumothorax. These adverse outcomes may be a marker of aggressive LAM.

Elsevier - Science Direct

http://www.sciencedirect.com/science?_o ... e5e8402ad9

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Pulmonary lymphangiomyomatosis diagnosed by video-assisted thoracic surgery; report of a case

Kyobu Geka. 2008 Nov

Shimizu Y, Tsunezuka Y, Tanaka N.
Department of General Thoracic Surgery, Ishikawa Prefectural Central Hospital, Kanazawa, Japan.

Pulmonary lymphangiomyomatosis (LAM) is a rare disease which occurs mainly in women of child-bearing age. The clinical characteristics of LAM include recurrent spontaneous pneumothorax, dyspnea on exertion, hemoptysis, chylothorax, and so on. A 41-year old woman was referred to our department for treatment of recurrent spontaneous pneumothorax. Chest computed tomography (CT) showed right pneumothorax and multiple small bullae located bilateral lung. These CT findings were most suggestive of LAM. To obtain a definitive diagnosis and treat pneumothorax, we performed a thoracoscopic lung biopsy, bullectomy, plication of bullae, and also performed mechanical and chemical pleurodesis. Histopathological examination of surgical specimen using immunohistochemical staining of HMB-45 and alpha-SMA revealed the proliferation of LAM cells, confirming a diagnosis of LAM. Here, we report a case that was diagnosed as LAM by thoracoscopic lung biopsy and treated by thoracoscopic surgery and pleurodesis.

PubMed

http://www.ncbi.nlm.nih.gov/pubmed/1904 ... d_RVDocSum

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Lung lymphangioleiomyomatosis (LAM)

Med Arh. 2008

Cukić V, Lovre V, Beslić S, Bilalović N, Guska S.
Klinika za plućne bolesti i TBC Podhrastovi, Sarajevo.

Lymphangioleiomyomatosis (LAM) is extreme rare diffuse lung disease of unknown cause seen almost exclusively in women of child-bearing age and rarely postmenopausal which indicates the involvement of hormones-estrogens. It results from proliferation of the cells having a smooth muscle cell phenotype (LAM cells) in the lung, and very often in the kidney and axial lymphatics and lymph nodes or any combination. It may occur sporadically or in association with the neurocutaneous syndrome--tuberous sclerosis. LAM cell proliferation may obstruct bronchioles, lymph vessels and venules that lead to airflow obstruction, formation of lung cysts, bullas and pneumothoraces, chylothorax, chylous ascites, hemosiderosis and hemoptysis. Approxymately 400 cases of LAM have been reported so far, most of them in USA. The average survival is about 8.5 years. There is no specific therapy. There are attempts with progesterone, lung transplantation, Doxycicline besides the symptomatic therapy. A new drug Rapamycin is tested. We are reporting 43-year old woman admitted in the Clinic for pulmonary diseases and TB "Podhrastovi" because of progressive dyspnea and suspect lung diffuse fibrosis, after the surgical treatment of spontaneous pneumothorax.The diagnosis of lung lymphangiomyomatosis was established by chest X ray, computerized chest tomography (CT), pathohistological findings of open lung biopsy. The treatment with progesterone is underway with other symptomatic therapy.

PubMed

http://www.ncbi.nlm.nih.gov/pubmed/1882 ... d_RVDocSum

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Lung transplantation for lymphangioleiomyomatosis: the French experience

Transplantation. 2008 Aug

Reynaud-Gaubert M, Mornex JF, Mal H, Treilhaud M, Dromer C, Quétant S, Leroy-Ladurie F, Guillemain R, Philit F, Dauriat G, Grenet D, Stern M.
The Divisions of Pulmonary Medicine and Thoracic Surgery, Hôpital Ste Marguerite, Marseille, France. martine.reynaud@ap-hm.fr

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare disease, leading in some cases to end-stage respiratory failure. Lung transplantation (LT) represents a therapeutic option in advanced pulmonary LAM. METHODS: We conducted a retrospective multicenter study of 44 patients who underwent LT for LAM at 9 centers in France between 1988 and 2006.

RESULTS: All patients were women with a mean age of 41+/-10 years at LT. There were 34 single-lung transplants and 11 bilateral transplants (one retransplantation). Prior clinical events related to LAM were present in 75% of the patients and previous thoracic surgical procedures were noted in 86.6% of cases. At the latest preoperative evaluation, 30 patients had an obstructive pattern (mean forced expiratory volume in 1 second: 26%+/-14% of predicted) and 15 had a combined restrictive and obstructive pattern, with a mean KCO=27%+/-8.8% of predicted, PaO2=52.8+/-10.4 and PaCO2=42.6+/-9.8 mm Hg. Intraoperative cardiopulmonary bypass was required in 13 cases. The length of mechanical ventilation was 7.5+/-12.8 days. The median duration of follow-up was 37 months. The 1, 2, 5, and 10 years survival rates were 79.6%, 74.4%, 64.7%, and 52.4%, respectively. Extensive pleural adhesions were found in 21 patients leading to severe intraoperative hemorrhage. Postoperative LAM-related complications were pneumothorax in the native lung in five patients, chylothorax in six, bronchial dehiscence or stenosis in seven. There were two cases of recurrence of LAM.

CONCLUSION: Despite a high morbidity mainly caused by previous surgical interventions and disease-related complications, LT is a satisfactory therapeutic option for end-stage respiratory failure in LAM.

Lipponcott, Williams & Wilkins

http://journals.lww.com/transplantjourn ... e=abstract

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Abdominal cystic tumor revealing lymphangioleiomyomatosis

Barbier L, Ebbo M, Andrac-Meyer L, Schneilitz N, Le Treut YP, Reynaud-Gaubert M, Hardwigsen J.
Service de chirurgie digestive et transplantation hépatique, hôpital de la Conception, 147, boulevard Baille, 13005 Marseille, France. louisebarbier@hotmail.fr

We report the case of a 39 year-old woman with many years of intermittent abdominal pain who was found to have cystic masses evocative of cystic lymphangioma involving the posterior mediastinal and retroperitoneum. Worsening abdominal pain led to a recommendation for laparoscopic unroofing and decompression of the cysts. During the postoperative period, hemorrhagic shock required reintervention with excision of the tumoral mass. Pathologic examination revealed lymphangioleiomyomatosis (LAM). On the 15th postoperative day, the patient developed a chylopneumothorax which required prolonged chest tube drainage. The presence of multiple polycystic lesions in the pulmonary parenchyma supported the diagnosis of diffuse LAM with primary extrapulmonary presentation. This diagnosis should be considered preoperatively since it modifies the treatment: a complete excision of the cystic lesions seems to be necessary in order to prevent bleeding and lymphatic extravasation.

Elsevier Science Direct

http://www.sciencedirect.com/science?_o ... 995fd06e66

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Serum vascular endothelial growth factor-D levels in patients with lymphangioleiomyomatosis reflect lymphatic involvement.

Chest. 2009 May

Glasgow CG, Avila NA, Lin JP, Stylianou MP, Moss J.
Translational Medicine Branch, Warren G Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892-1590, USA.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare multisystem disorder affecting primarily women of child-bearing age, and characterized by cystic lung destruction, tumors of the kidney (angiomyolipomas [AMLs]), and involvement of the axial lymphatics (lymphangioleiomyomas). Patients with LAM experience loss of pulmonary function attributed to the proliferation of abnormal-appearing smooth muscle-like cells (LAM cells). It is possible to group the LAM population by the presence or absence of extrapulmonary involvement (eg, AMLs, lymphangioleiomyomas, chylous effusions). Serum vascular endothelial growth factor (VEGF)-D, a lymphangiogenic factor, is higher in LAM patients than in healthy volunteers and has been proposed as a tool in the differential diagnosis of cystic lung disease. We assessed serum VEGF-D concentrations in relationship to clinical phenotype in LAM patients.

METHODS: Serum VEGF-D levels were quantified by enzyme immunosorbent assay for 111 patients with LAM and 40 healthy volunteers. VEGF-D levels in patients with pulmonary LAM, with or without extrapulmonary manifestations, were compared to those of healthy volunteers.

RESULTS: Serum VEGF-D levels were greater in patients with LAM compared to those of healthy volunteers (p < 0.001). However, when patient samples were grouped based on the extent of lymphatic extrapulmonary involvement (eg, lymphangioleiomyomas and adenopathy), the statistical difference was maintained only for patients with LAM with lymphatic involvement (p < 0.001), not for those patients whose disease was restricted to the lung. Serum VEGF-D levels are a good biomarker for lymphatic involvement (area under the curve [AUC], 0.845; p < 0.0001), and a fair predictor for LAM disease (AUC, 0.751; p < 0.0001). Serum levels correlated to CT scan grade (p = 0.033).

CONCLUSIONS: Serum VEGF-D concentration is a measure of lymphatic involvement in patients with LAM.

Chest Journal - Chest Foundation.org

http://www.chestjournal.org/content/135/5/1293.long

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TSC1 and TSC2 mutations in patients with lymphangioleiomyomatosis and tuberous sclerosis complex.

Muzykewicz DA, Sharma A, Muse V, Numis AL, Rajagopal J, Thiele EA.
BACKGROUND: Lymphangioleiomyomatosis (LAM) is a prominent finding in the setting of tuberous sclerosis complex (TSC). OBJECTIVE: The present study was designed to compare cystic lung changes consistent with LAM in patients with a TSC1 disease-causing mutation, TSC2 disease-causing mutation, or no mutation identified (NMI). METHODS AND RESULTS: We conducted a retrospective review of the chest computed tomography (CT) of 45 female and 20 male patients with TSC and found cysts consistent with LAM in 22 (49%) women and two (10%) men. In the female population, changes consistent with LAM were observed in six of 15 (40%) patients with TSC1, 11 of 23 (48%) with TSC2, and five of seven (71%) with NMI. While the predominant size of cysts did not differ across these three groups, TSC2 women with LAM had a significantly greater number of cysts than did TSC1 patients (p = 0.010). CONCLUSIONS: These findings suggest a higher rate of LAM in TSC1 than previously recognised, as well as a fundamental difference in CT presentation between TSC1 and TSC2.

British Medical Journal

http://jmg.bmj.com/cgi/content/full/46/7/465
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Re: Lymphangioleiomyomatosis (LAM)

Postby patoco » Sat Sep 17, 2011 10:48 am

Current management of lymphangioleiomyomatosis.

Taillé C, Borie R, Crestani B.

Source

Service de Pneumologie et Centre de Compétence des Maladies Pulmonaires Rares, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Université Paris Diderot, Paris, France.

Abstract

PURPOSE OF REVIEW:

Lymphangioleiomyomatosis (LAM) is a rare but devastating disease, leading to chronic respiratory failure. Considerable progress for comprehension of the disease has been made when mutations of the tuberous sclerosis genes TSC1 and TSC2, were discovered in LAM cells. Therapeutic consequences of these studies are important, leading to clinical trials with sirolimus for LAM.

RECENT FINDINGS:
In two studies, angiomyolipoma size decreased by 26-50% after 12 months of sirolimus treatment. In a recent 12 months controlled trial involving 89 patients with pulmonary LAM, sirolimus stopped lung function decline and improved quality of life and performance score. The protective effect of sirolimus was lost after treatment discontinuation, with a parallel lung function decline in both groups, similar to the increase in angiomyolipoma size. Sirolimus is associated with an excess of adverse events.

SUMMARY:
Sirolimus represents an important drug for LAM that should be proposed to patients with a rapid alteration of lung function or with a significant clinical impairment, after individual evaluation of the risk/benefit ratio. Sirolimus seems to have a sharper effect on the reduction of abdominal masses than on lung cysts. Tolerance and safety concerns are serious limits to the long-term treatment of patients with sirolimus.

Lippincott, Williams and Wilkins

http://journals.lww.com/co-pulmonarymed ... e=abstract
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Re: Lymphangioleiomyomatosis (LAM)

Postby patoco » Mon Jan 23, 2012 10:01 am

Giant bilateral renal angiomyolipomas and lymphangioleiomyomatosis presenting after two successive pregnancies successfully treated with surgery and rapamycin.
2011

Peces R, Cuesta-López E, Peces C, Selgas R.

Source

Servicio de Nefrología, Hospital Universitario La Paz, IdiPAZ, 28046 Madrid, Spain. cpeces@varnetmail.com

Abstract

Keywords: Angiomyolipomas, lymphangioleiomyomatosis, nephrectomy, mTOR, pregnancy, tuberous sclerosis complex

We report the case of a 25-year-old woman who presented with abdominal and flank pain with two successive pregnancies and was diagnosed of giant bilateral renal AMLs and pulmonary LAM associated with TSC in the post-partum of her second pregnancy. This case illustrates that in women with TSC rapid growth from renal AMLs and development of LAM may occur with successive pregnancies. It also stresses the potential for preservation of renal function despite successive bilateral renal surgery of giant AMLs. Moreover, the treatment with a low-dose rapamycin may be an option for LAM treatment. Finally, a low-dose rapamycin may be considered as an adjuvant treatment together to kidney-sparing conservative surgery for renal AMLs.

http://www.ncbi.nlm.nih.gov/pmc/article ... ool=pubmed

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Successful pregnancy complicated by persistent pneumothorax in a patient with lymphangioleiomyomatosis (LAM) on sirolimus.

Faehling M, Frohnmayer S, Leschke M, Trinajstic-Schulz B, Weber J, Liewald F.

Source

Klinik für Kardiologie und Pneumologie, Klinikum Esslingen, Esslingen; 2Lungenfacharztpraxis, Esslingen.

m.faehling@klinikum-es.de

Abstract
We report a successful pregnancy in a patient with longstanding LAM on treatment with sirolimus. During temporary discontinuation fo sirolimus in early pregnancy, lung function declined but recovered after resumption of sirolimus. Pregnancy was complicated by a persistent pneumothorax which was treated surgically postnatally. The child has had a normal development despite exposure to low dose sirolimus intermittently during early embryonal and mid-fetal life.

http://www.ncbi.nlm.nih.gov/pubmed/22117507

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Prevalence of uterine and adnexal involvement in pulmonary lymphangioleiomyomatosis: a clinicopathologic study of 10 patients.

Dec 2011

Hayashi T, Kumasaka T, Mitani K, Terao Y, Watanabe M, Oide T, Nakatani Y, Hebisawa A, Konno R, Takahashi K, Yao T, Seyama K.

Source

Departments of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan.

Abstract

Lymphangioleiomyomatosis (LAM), a systemic disorder affecting almost exclusively young women, is characterized by the abnormal proliferation of smooth muscle-like cells (LAM cells). LAM can occur either in association with the tuberous sclerosis complex (TSC) (TSC-LAM) or without TSC (sporadic LAM). Recent studies have demonstrated that LAM is a neoplasm arising from constitutive activation of the mammalian target of rapamycin signaling pathway dysregulated by a functional loss of TSC genes, but the primary organ of origin remains unclear. Therefore, we performed histologic and immunohistologic analyses of gynecologic organs in 20 patients, half with and the other half without pulmonary LAM, to determine how often LAM involves the uterus. The results showed that 9 of 10 (90%) patients with pulmonary LAM had uterine LAM lesions. In contrast, no patients without pulmonary LAM had so. All uterine LAM lesions were accompanied by LAM lesions in retroperitoneal or pelvic lymph nodes and LAM cell clusters, each enveloped by a monolayer of vascular endothelial growth factor receptor-3-positive lymphatic endothelial cells. Furthermore, when we compared uterine lesions of TSC-LAM with those of sporadic LAM, proliferation of HMB45-positive epithelioid-shaped LAM cells and infiltrates with a tongue-like growth pattern was more prominent in the former, whereas the extent of lymphangiogenesis within the myometrium was greater in the latter. These results indicate that uterine involvement is a common manifestation of LAM, and, possibly, that the uterus or an adjacent locale in the retroperitoneum or pelvic cavity is the primary site of origin of LAM.

http://journals.lww.com/ajsp/pages/arti ... e=abstract

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A CURRENT VIEWPOINT OF LYMPHANGIOLEIOMYOMATOSIS SUPPORTING IMMUNOTHERAPEUTIC TREATMENT OPTIONS.

Sep 2011

Dilling DF, Gilbert ER, Picken MM, Eby J, Love RB, Le Poole IC.

Source

Medicine, Loyola University Chicago, Maywood, Illinois, United States.

Abstract

Lymphangioleiomyomatosis (LAM) leads to hyperproliferation of abnormal smooth muscle cells in the lungs, associated with diffuse pulmonary parenchymal cyst formation and progressive dyspnea on exertion. The disease targets women of child-bearing age. Complications include pneumothoraces and chylous pleural effusions. Ten-year survival is estimated at 70% and currently, lung transplantation remains the only validated treatment. It has been observed that LAM cells express markers associated with melanocytic differentiation, including gp100 and MART1. Other melanocytic markers have also been observed. The same proteins are targeted by T cells infiltrating melanoma tumors as well as by T cells infiltrating autoimmune vitiligo skin, and these antigens are regarded as relatively immunogenic. Consequently, vaccines have been developed for melanoma targeting these and other immunogenic melanocyte differentiation proteins. Preliminary data showing susceptibility of LAM cells to melanoma-derived T cells suggest that vaccines targeting melanosomal antigens can be successful to treat LAM.

Full Text Article

http://ajrcmb.atsjournals.org/content/e ... 215TR.long

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Use of variability in national and regional data to estimate the prevalence of lymphangioleiomyomatosis.
Nov 2011

Harknett EC, Chang WY, Byrnes S, Johnson J, Lazor R, Cohen MM, Gray B, Geiling S, Telford H, Tattersfield AE, Hubbard RB, Johnson SR.

Source

Division of Therapeutics and Molecular Medicine and Respiratory Biomedical Research Unit, University of Nottingham, Nottingham, UK.

Abstract

BACKGROUND:
Understanding the true prevalence of lymphangioleiomyomatosis (LAM) is important in estimating disease burden and targeting specific interventions. As with all rare diseases, obtaining reliable epidemiological data is difficult and requires innovative approaches.

AIM:
To determine the prevalence and incidence of LAM using data from patient organizations in seven countries, and to use the extent to which the prevalence of LAM varies regionally and nationally to determine whether prevalence estimates are related to health-care provision.

METHODS:
Numbers of women with LAM were obtained from patient groups and national databases from seven countries (n = 1001). Prevalence was calculated for regions within countries using female population figures from census data. Incidence estimates were calculated for the USA, UK and Switzerland. Regional variation in prevalence and changes in incidence over time were analysed using Poisson regression and linear regression.

RESULTS:
Prevalence of LAM in the seven countries ranged from 3.4 to 7.8/million women with significant variation, both between countries and between states in the USA. This variation did not relate to the number of pulmonary specialists in the region nor the percentage of population with health insurance, but suggests a large number of patients remain undiagnosed. The incidence of LAM from 2004 to 2008 ranged from 0.23 to 0.31/million women/per year in the USA, UK and Switzerland.

CONCLUSION:
Using this method, we have found that the prevalence of LAM is higher than that previously recorded and that many patients with LAM are undiagnosed.

http://qjmed.oxfordjournals.org/content ... 1.abstract

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Bacteriologically confirmed pulmonary tuberculosis in a patient with lymphangioleiomyomatosis accompanying tuberous sclerosis syndrome
2011

http://www.ncbi.nlm.nih.gov/pubmed/21678282

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Prevalence of uterine leiomyomas in lymphangioleiomyomatosis.
Sept 2011

Key Words: Uterine leiomyomas, hysterectomy, lymphangioleiomyomatosis

http://www.fertstert.org/article/S0015-0282(11)01015-6/abstract

Autophagy: an 'Achilles' heel of tumorigenesis in TSC and LAM.

http://www.landesbioscience.com/journal ... =901466549

Is sirolimus a therapeutic option for patients with progressive pulmonary lymphangioleiomyomatosis?

May 2011

Neurohr C, Hoffmann AL, Huppmann P, Herrera VA, Ihle F, Leuschner S, von Wulffen W, Meis T, Baezner C, Leuchte H, Baumgartner R, Zimmermann G, Behr J.

Department of Int, Medicine I, Division of Pulmonary Diseases, Klinikum Grosshadern, Ludwig-Maximilians University, Comprehensive Pneumology Center, Marchioninistrasse 15, 81377 Munich, Germany. claus.neurohr@med.uni-muenchen.de

Abstract

BACKGROUND:
Lymphangioleiomyomatosis (LAM) is a rare lung disease characterised by progressive airflow obstruction. No effective medical treatment is available but therapy with sirolimus has shown some promise. The aim of this observational study was to evaluate sirolimus in progressive LAM.

METHODS:
Sirolimus (trough level 5 - 10 ng/ml) was administered to ten female patients (42.4 ± 11.9 years) with documented progression. Serial pulmonary function tests and six-minute-walk-distance (6-MWD) assessments were performed.

RESULTS:
The mean loss of FEV1 was -2.30 ± 0.52 ml/day before therapy and a significant mean gain of FEV1 of 1.19 ± 0.26 ml/day was detected during treatment (p = 0.001). Mean FEV1 and FVC at baseline were 1.12 ± 0.15 l (36.1 ± 4.5%pred.) and 2.47 ± 0.25 l (69.2 ± 6.5%pred.), respectively. At three and six months during follow-up a significant increase of FEV1 and FVC was demonstrated (3 months ΔFEV1: 220 ± 82 ml, p = 0.024; 6 months ΔFEV1: 345 ± 58 ml, p = 0.001); (3 months ΔFVC: 360 ± 141 ml, p = 0.031; 6 months ΔFVC: 488 ± 138 ml, p = 0.006). Sirolimus was discontinued in 3 patients because of serious recurrent lower respiratory tract infection or sirolimus-induced pneumonitis. No deaths and no pneumothoraces occurred during therapy.

CONCLUSIONS:
Our data suggest that sirolimus might be considered as a therapeutic option in rapidly declining LAM patients. However, sirolimus administration may be associated with severe respiratory adverse events requiring treatment cessation in some patients. Moreover, discontinuation of sirolimus is mandatory prior to lung transplantation.

Full Text Article

http://www.ncbi.nlm.nih.gov/pmc/article ... ool=pubmed
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