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European Respiratory Society Guidelines for the diagnosis and management of lymphangioleiomyomatosis (LAM)
Editorial

The European lymphangioleiomyomatosis (LAM) Taskforce, supported by the European Respiratory Society, is working on the production of guidelines for the diagnosis and management of LAM aiming in the standardisation of diagnostic criteria and patient management. This may further improve clinical care and facilitate research and clinical trials of new treatments.

Therefore, the taskforce has two aims:

1.  To produce evidence-based, consensus guidelines for the diagnosis, assessment, and treatment of patients with LAM.

2.  To establish the basis for a European LAM network with participants from the European countries in order to establish and consolidate registries and cohorts for clinical studies and therapeutic trials.

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 surgery, 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 Societies (Table 1).

TABLE 1. Taskforce members of the ers lam guidelines.

Chairmen:
Simon Johnson and Jean-François Cordier

Core Panel:
Romain Lazor, Vincent Cottin (Secretary), Sergio Harari, Ulrich Costabel

Consultant panel:
Michel Brauner (Imaging), Martine Reynaud-Gaubert (Transplantation), Annette Boehler (Transplantation), Franco Bonetti (Pathology), Helmut Popper (Pathology), Christopher Kingswood (Tuberous sclerosis)

Review panel:
Carlo Albera, John Bissler, Demosthenes Bouros, Paul Corris, John Dark, Seamas Donnelly, Roland du Bois, Corine Durand, Jim Egan, Jan Grutters, Ulla Hodgson, Gill Hollis, Maria Korzeniewska, Jan Kus, Jacques Lacronique, Jan-Willem Lammers, Ana Cristina Mendes, Anne Naalsund, Olivier Rouvière, Wolfgang Pohl, Jay Ryu, Julian Sampson, Anne Tattersfield, William Travis, Pentti Tukiainen, Thierry Urban, Dominique Valeyre, Geert Verleden.

The contents of the report are shown in Table 2.

TABLE 2. The contents of the report:

  1. SUMMARY

   2. INTRODUCTION

   3. METHODS

   4. LYMPHANGIOLEIOMYOMATOSIS (LAM): DESCRIPTION OF DISEASE

        1. Respiratory manifestations

        2. Lymphatic manifestations

        3. Renal manifestations

        4. Meningioma

        5. LAM in tuberous sclerosis complex (TSC)

        6. Pathology

   5. RECOMMENDATIONS FOR DIAGNOSIS AND WORKUP OF PATIENTS WITH LAM

        1. Diagnostic criteria

        2. Pathologic criteria for diagnosis

        3. Radiological criteria for diagnosis

        4. Screening for meningioma

        5. Workup for TSC in patients with LAM

        6. Screening for pulmonary hypertension

        7. Lung function testing

        8. Arterial blood gas measurements

        9. Cardiopulmonary exercise testing and six minute walk test

   6. SCREENING FOR LAM IN AT RISK GROUPS

        1. Women with apparently spontaneous pneumothorax

        2. Women with TSC and no respiratory symptoms

        3. Women with TSC and respiratory symptoms

        4. Men with TSC

        5. Women with angiomyolipoma

   7. PROGNOSIS

   8. MANAGEMENT

      General advices and interventions

          1. Pneumothorax

          2. Pregnancy

          3. Oestrogen avoidance

          4. Air travel

          5. Follow up of asymptomatic TSC-LAM

          6. Pulmonary rehabilitation

          7. Influenza and pneumococcal vaccination

          8. Osteoporosis

        Drug treatment

          9. Bronchodilators

        10. Progesterone

         11. Other anti-oestrogen measures

         12. mTOR inhibitors

      Complications and co-morbidities

         13. Pneumothorax

         14. Chylothorax

         15. Angiomyolipoma: treatment and follow up

         16. Angiomyolipoma: management in asymptomatic patients

        Lung transplantation

         17. Referral criteria

         18. Choice of procedure

         19. Special considerations in TSC

         20. Angiomyolipoma and transplantation

         21. Investigation of recurrent LAM

         22. Post-transplant immunosuppression regimen

LAM is an orphan lung disease, which occurs sporadically or in association with the genetic disease tuberous sclerosis complex (TSC)1,2. LAM is associated with defective function of either TSC1 or more commonly TSC2 genes in affected cells resulting in uncontrolled proliferation and migration3. Sporadic LAM affects approximately 1:400,000 adult women. TSC-LAM occurs in 30-40% of adult women4,5 and exceptionally in men and children6.

LAM usually appears with progressive dyspnoea, recurrent pneumothorax, chylous collections, and occasionally haemoptysis, and rarely is asymptomatic1-2. Extra pulmonary complications of LAM include lymphadenopathy and cystic masses of the axial lymphatics termed lymphangioleiomyomas, which result in abdominal and pelvic lymphatic obstruction1-2. LAM is associated with angiomyolipoma, a benign tumour generally occurring in the kidneys, and an increased frequency of meningioma. 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 showing characteristic LAM cell morphology and positive immunoreactivity to smooth muscle actin and HMB-45 antibodies, and/or a combination of history and high resolution computed tomography (HRCT); however, a number of conditions with multiple pulmonary cysts can mimic LAM and the reliability of this approach has not been studied. The proposed diagnostic criteria, still under discussion, are shown in table 3.

TABLE 3. Diagnostic criteria

DEFINITE LAM

1.   Characteristica or compatibleb HRCT

     and

     lung biopsy fitting the pathological criteria for LAMc

     OR

2.   Characteristica HRCT and any of the following:

     - angiomyolipoma (kidney)d

     - thoracic or abdominal chylous effusione

     - lymphangioleiomyomaf or lymph-node involved by LAMf

     - definite or probable TSCg

PROBABLE LAM

1.   Characteristic HRCT and compatible clinical historyh

     OR

2.   Compatible b HRCT and any of the following:

     - angiomyolipoma (kidney)d

     - thoracic or abdominal chylous effusione

POSSIBLE LAM

Characteristic a or compatible b HRCT

Abbreviations:

a.    characteristic HRCT consists of multiple, bilateral, thin-walled round well-defined air-filled cysts with preserved or increased lung volume with no other significant pulmonary involvement especially interstitial lung disease with the exception of possible features of multifocal micronodular pneumocyte hyperplasia in patients with TSC

b.    compatible HRCT consists of only few multiple (>2 and ≤10) thin-walled round well-defined air-filled cysts (less than 30 mm) with preserved or increased lung volume with no other significant pulmonary involvement especially interstitial lung disease with the exception of possible features of multifocal micronodular pneumocyte hyperplasia in patients with TSC

c.    as described in the text

d.    diagnosed by characteristic CT features and/or on pathological examination (after complete or partial resection)

e.    based on visual and/or biochemical characteristics of the chylous character of effusion

f.     based on pathological examination

g.    appendix section xx (with pulmonary features not taken into account for the diagnosis of TSC)

h.    compatible clinical features includes pneumothorax (especially multiple and/or bilateral and/or relapsing), chylous effusion, and/or altered lung function tests as in LAM

There have been no controlled trials of its management which varies from centre to centre. Supportive treatment includes management of airflow obstruction and hypoxemia, treatment of pleural complications, and interventional treatment of symptomatic renal lesions. 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, has led to trials of mTOR inhibitors including Sirolimus7,8.

REFERENCES

    1. Johnson S. Rare diseases. 1. Lymphangioleiomyomatosis: clinical features, management and basic mechanisms. Thorax 1999;54:254-64.

    2. Pigakis K, Meletis G, Ferdoutsis M, Patsourakis G, Bahlitzanakis N, Triantafillou L. Lymphangioleiomyomatosis in Tuberous Sclerosis. PNEUMON 2008;21:254-272.

    3. Carsillo T, Astrinidis A, Henske EP. Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. Proc Natl Acad Sci USA 2000;97(11):6085-90.

    4. Urban T, Lazor R, Lacronique J, et al. Pulmonary lymphangioleiomyomatosis. A study of 69 patients. Groupe d'Etudes et de Recherche sur les Maladies "Orphelines" Pulmonaires (GERM"O"P). Medicine (Baltimore) 1999;78(5):321-37.

    5. Johnson SR, Tattersfield AE. Decline in lung function in lymphangioleiomyomatosis: relation to menopause and progesterone treatment. Am J Respir Crit Care Med 1999;160(2):628-33.

    6. Aubry MC, Myers JL, Ryu JH, et al. Pulmonary lymphangioleiomyomatosis in a man. Am J Respir Crit Care Med 2000;162(2 Pt 1):749-52.

    7. Bissler JJ, McCormack FX, Young LR, et al. Sirolimus for Angiomyolipoma in Tuberous Sclerosis Complex or Lymphangioleiomyomatosis. N Engl J Med %R 10.1056/NEJMoa063564 2008;358(2):140-151.

    8. Davies DM, Johnson SR, Tattersfield AE, et al. Sirolimus Therapy in Tuberous Sclerosis or Sporadic Lymphangioleiomyomatosis. N Engl J Med %R 10.1056/NEJMc072500 2008;358(2):200-203.

 

© 2011 PNEUMON Magazine, Hellenic Bronchologic Society.
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