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«European Respiratory Society Guidelines for the diagnosis and management of lymphangioleiomyomatosis (LAM) S.R. Johnson1, J.F. Cordier2, R. Lazor3,2, ...»

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European Respiratory Society Guidelines for the

diagnosis and management of

lymphangioleiomyomatosis (LAM)

S.R. Johnson1, J.F. Cordier2, R. Lazor3,2, V. Cottin2, U. Costabel4, S. Harari5, M. Reynaud-

Gaubert6, A. Boehler7, M. Brauner8, H. Popper9, F. Bonetti10, C. Kingswood11, and the Review

panel of the ERS LAM Task Force

1. SR. Johnson, Division of Therapeutics and Molecular Medicine, University of Nottingham,

Queens Medical Centre, Nottingham, United Kingdom

2. J.F. Cordier, V. Cottin, R. Lazor, Reference Center for Rare Pulmonary Diseases, Claude Bernard University, UMR 754, University of Lyon, France

3. R. Lazor, Clinic for interstitial and rare lung diseases, Department of Respiratory Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

4. U. Costabel, Pneumologie/Allergologie, Ruhrlandklinik, Universitätsklinikum, Essen, Germany

5. S. Harari, Unità di Pneumologia, Ospedale San Giuseppe AFAR, Milan, Italy

6. M. Reynaud-Gaubert, Division of Pulmonary Medicine and Thoracic Surgery, Sainte Marguerite University Hospital, Marseille, France

7. A. Boehler, Pulmonary Medicine and Lung Transplant Program, University Hospital, Zurich, Switzerland

8. M. Brauner, Service de radiologie, Hôpital Avicenne, Université Paris-13, Bobigny, France

9. H. Popper, Institute of Pathology, University of Graz, Austria

10. F. Bonetti, Policlinico B. Roma, Universita di Verona, Verona, Italy

11. C. Kingswood, Royal United Hospital, Bath, United Kingdom

Correspondence :

J.F. Cordier (Co-chair) Department of Respiratory Medicine –Reference Center for Rare Pulmonary Diseases Louis Pradel University Hospital 69677 Lyon (Bron), France Fax : 33 4 72 35 76 53 E-mail : jean-francois.cordier@chu-lyon.fr S.R. Johnson (Co-chair) Division of Therapeutics and Molecular Medicine, University of Nottingham Queens Medical Centre Nottingham. NG7 2UH UK Fax: +44 115 8231059 E-mail: simon.johnson@nottingham.ac.uk

Task Force Review panel :

C. Albera, University of Turin, Department of Clinical and Biological Sciences, San Luigi Gonzaga Medical School, Interstitial and Rare Lung Disease Center, Orbassano (Turin), Italy J. Bissler, Division of Nephrology and Hypertension, Children's Hospital Research Foundation, Cincinnati, USA D. Bouros, Department of Pneumonology, University Hospital of Alexandroupolis, Alexandroupolis, Greece P. Corris, Department of Respiratory Medicine, Freeman Hospital, High Heaton Newcastle upon Tyne, United Kingdom S. Donnelly, St. Vincent's University Hospital, Dublin, Ireland C. Durand, France Lymphangioleiomyomatosis (FLAM), Saint Benoit, France J. Egan, Dept of Respiratory Medicine, Mater Misericordiae Hospital, Dublin, Ireland J.C. Grutters, Department of Pulmonology, St Antonius Hospital, Nieuwegein, The Netherlands U. Hodgson, Pulmonary Clinic, Helsinki University Central Hospital, Huch, Finland G. Hollis, LAM Action, Nottingham, United Kingdom M. Korzeniewska-Kosela, National Tuberculosis and Lung Diseases Research Institute, Warsaw,

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J. Kus, Department of Pulmonary Diseases, National Tuberculosis and Lung Diseases Research Institute, Warsaw, Poland J. Lacronique, Department of Pneumology, Cochin University Hospital, Paris, France J.W. Lammers, Division of Heart & Lungs, University Medical Center Utrecht, Utrecht, The Netherlands F. McCormack, Division of Pulmonary and Critical Care, University of Cincinnati, Cincinnati, USA A.C. Mendes, Department of Pneumology, Santa Maria Hospital,Llisboa, Portugal J. Moss, Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland USA A. Naalsund, Department of Respiratory Medicine, Rikshospitalet, Oslo, Norway W. Pohl, Department of Pneumology, Krankenhaus Hietzing, Vienna, Austria E. Radzikowska, National Tuberculosis and Lung Diseases Research Institute, Warsaw, Poland C. Robalo-Cordeiro, Department of Pneumology, University Hospital of Coimbra, Coimbra, Portugal O. Rouvière, Department of Urinary and Vascular Radiology, Hôpital E. Herriot, Hospices Civils de Lyon, Université Lyon 1, France J. Ryu, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, USA M. Schiavina, Department of Pneumology, Policlinico S.Orsola-Malpighi, Bologna, Italy A.E. Tattersfield, Division of Respiratory Medicine, Nottingham City Hospital, Nottingham, UK W. Travis, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA P. Tukiainen, Department of Pulmonary Diseases, University Central Hospital, Helsinki, Finland T. Urban, Department of Pneumology, Angers University Hospital, Angers, France D. Valeyre, Department of Pneumology, Avicenne Hospital, Bobigny, France G.M. Verleden, Department of Respiratory Diseases, University Hospital Gasthuisberg, Leuven, Belgium

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Lymphangioleiomyomatosis (LAM) is an orphan lung disease, which occurs sporadically or in association with the genetic disease tuberous sclerosis complex (TSC)[1, 2]. Sporadic LAM is rare, affecting approximately 1:400,000 adult women; whereas in TSC, LAM occurs in 30-40% of adult women[3, 4] and exceptionally in men and children[5, 6].

Although some are asymptomatic, patients with LAM usually develop progressive dyspnoea, recurrent pneumothorax, chylous collections and occasionally haemoptysis[1]. Extrapulmonary complications of LAM include lymphadenopathy and cystic masses of the axial lymphatics termed lymphangioleiomyomas which may result in abdominal and pelvic lymphatic obstruction[7]. LAM is often associated with angiomyolipoma, a benign tumour generally occurring in the kidneys[8], and an increased frequency of meningioma[9]. LAM is highly variable in terms of clinical features and rate of progression: this together with an absence of clear prognostic factors results in patients being given conflicting information about their prognosis.

Diagnosis is made by tissue biopsy and/or a combination of history and computed tomography (CT) scanning. Tissue biopsy is generally from the lung, especially when surgical procedures for

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lymphangioleiomyomas are sampled. Pathological diagnosis is reliant on characteristic LAM cell morphology and positive immunoreactivity to smooth muscle actin and HMB-45 antibodies.

Increasingly high resolution CT scanning (HRCT) is used to diagnose LAM without resorting to lung biopsy; however a number of conditions with multiple pulmonary cysts can mimic LAM and the reliability of this approach has not been studied.

As LAM is rare, there have been no controlled trials of its management which varies from centre to centre. Supportive treatment includes management of airflow obstruction and hypoxaemia with

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including pneumo- and chylothorax, and interventional treatment of renal lesions[10, 11]. As LAM is a disease of women and is thought to be accelerated by oestrogen: oophorectomy, tamoxifen, progesterone and gonadotropin-releasing hormone (GnRH) analogues have been used although there is no evidence that any are effective. More recently the finding of abnormalities in the TSC1/2 genes resulting in constitutive activation of the kinase mammalian target of rapamycin (mTOR)[12, 13] has led to trials of mTOR inhibitors including sirolimus in patients with LAM and angiomyolipoma[14, 15].

The purpose of the LAM Task Force was to produce evidence based, consensus guidelines for the diagnosis, assessment, and treatment of patients with LAM.

METHODS The two Chairmen (S. Johnson and J.F. Cordier) designed the objectives of the LAM Taskforce, submitted the project to the European Respiratory Society for sponsorship, contacted recognised specialists with competence in LAM to participate in the Core and Consultant panels, and organised the process of elaborating guidelines through face to face meetings and electronic communication.

The working party was composed of three panels. The Core panel had overall responsibility for the guidelines and developing the project. The Consultant panel advised on specialist aspects of the guidelines including lung transplantation, pathology, and tuberous sclerosis. The Review panel reviewed the documents and comprised all members of the Core and consultant panels plus international experts in LAM, interstitial lung diseases, and representatives of European Thoracic

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The process of guideline development was as follows: 1) question formulation, 2) evidence collection and synthesis (Core and Consultant panels), 3) grading of recommendation strength using the 2004 American College of Chest Physicians health and science policy grading system[16] (Core and Consultant panels), 4) circulation of documents and first version of the guidelines (Core and Consultant panels), 5) first formal review with scoring of agreement and proposals for modifications using Likert scale statistics and definitions[17] (Core, Consultant and Review panels), 6) integration of proposals (Core panel), 7) second formal review with reassessment of agreement (Core, Consultant and Review panels), and 8) final revision (Core panel). Final recommendations are scored by 1) strength of recommendation: (grade) from A (strongest) to D (weakest) and I (inconclusive), 2) quality of evidence (quality) 3), magnitude of benefit, and 4) strength of expert consensus. Further details are contained in appendix 1.


Respiratory manifestations Symptoms In most cases of LAM respiratory manifestations dominate the clinical picture.

Dyspnoea is the most common symptom occurring in almost all patients and is the presenting feature in 42% of cases (Table 1). In many cases dyspnoea is associated with wheeze and cough and may be caused by replacement of the lung parenchyma by cysts, by airflow obstruction, and by the presence of pneumothorax or chylous pleural effusions. Cough is generally dry in the early stages of LAM although patients with more advanced disease may produce sputum and have recurrent infections. A small number of patients have intermittent, mild, haemoptysis and others cough sticky white secretions, which probably represent chyloptysis. Pneumothorax appears the most common mode of presentation and is bilateral in up to 4% of patients[18]. Pneumothorax is

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Physical findings There are generally no positive physical findings in patients with early disease unless pneumothorax or chylous effusion is the presenting problem. In those with more advanced disease, signs of lung hyperinflation, wheezing and cyanosis may be present. Signs of TSC (appendix 2) may be present in those with TSC-LAM.

Physiological tests Patients with LAM develop airflow obstruction and impaired gas transfer with preserved lung volumes. Early studies featured patient cohorts who had more advanced disease and the majority of these patients had abnormal spirometry and gas transfer[20, 25]. More recent studies using national cohorts have included more patients with mild or early disease (table 2). In two such studies, TLCO was within the normal range in 18% of 80 patients whereas FEV1 was normal in 42% of 45 patients[3, 8]. Lung function, particularly TLCO and FEV1 have been correlated with histological[26] and CT grading of disease severity[27] and used to assess disease progression in large series of patients. Patients with LAM have limitation of their exercise performance. Cardiopulmonary exercise testing has shown that maximal oxygen uptake during exercise (VO2max) correlated well with TLCO, extent of disease on CT[28] and was more sensitive at detecting early disease than standard lung function[28].

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Radiological findings The chest radiograph may be normal in early disease although in the majority of cases cysts, bullae, reticulonodular shadows and hyperinflation are present with pneumothorax and pleural effusion also seen (table 3). Multiple, round, thin-walled, well-defined air-filled cysts with preserved or increased lung volume are seen in all patients with LAM examined by HRCT (figure 1a).

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Lymphatic manifestations The axial lymphatics of the thorax, retroperitoneum, abdomen, and pelvis may become thickened, dilated and in some cases occluded by LAM cells[19, 31]. This results in lymphadenopathy in 40% of patients[7] and enlarged cystic lymphatic collections termed lymphangioleiomyomas in 21% of patients[7, 32]. Symptoms are rare in patients with abdomino-pelvic lymphadenopathy.

45% of those with lymphangioleiomyomas develop symptoms including palpable masses, abdominal discomfort, bloating, leg oedema, paresthaesia and local pressure symptoms,

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occasionally described although are rarely clinically significant. In addition approximately 7% of patients develop chyloptysis, presumably due to occlusion of lung parenchymal lymphatics[24].

Chyluria, occurring by a similar mechanism in the bladder has also been observed[35].

Renal manifestations Angiomyolipomas are benign tumours consisting of smooth muscle (LAM) cells, blood vessels and fat (figure 1b). Angiomyolipomas occur in up to 50% of patients with sporadic LAM, 69of patients with TSC[36-39] and almost all patients with TSC-LAM[40]. The majority of angiomyolipomas are less than 1.5 cm but in some patients, especially those with TSC, angiomyolipomas may enlarge and multiple tumours can occur in both kidneys[41]. Tumours greater than 4 cm, particularly those with aneurysmal vessels are prone to bleeding, presenting as haematuria and haemoperitoneum. During the course of the disease further angiomyolipomas may develop or enlarge. TSC is associated with other renal lesions including renal cysts and polycystic kidney disease that may result in chronic renal failure[22, 38, 39, 42-46].

Meningioma Both sporadic and TSC-LAM are associated with an increased risk of meningioma. Meningioma has been reported in case reports[47-49] and in a study of 250 patients was detected by screening in 9 patients (3.6%), three of whom were symptomatic[9, 50].

TSC-LAM The recent observations that 26-39% of adult women with TSC have lung cysts consistent with LAM[2, 51, 52] but less than 3% have symptoms of LAM[53] suggests that a large number of

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