What is LAM and How Should It Be Managed
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Thank you for viewing this presentation.
We would like to remind you that this
material is the property of the author.
It is provided to you by the ERS for your
personal use only, as submitted by the
author.
2014 by the author
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Sergio Harari
U.O. di Pneumologia e UTIR
Servizio di Emodinamica e Fisiopatologia Respiratoria
Ospedale San Giuseppe MultiMedica - Milano
What is LAM and how should it be managed?
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Lymphangioleiomyomatosis (LAM)
Lymphangioleiomyomatosis (LAM) is a rare multisystem disorder
affecting predominantly young females in their reproductive years.
It is characterised by progressive cystic destruction of the lung,
lymphatic abnormalities and abdominal tumours (e.g. renal
angiomyolipomas, lymphangioleiomyomas)
It can be sporadic or associated with TSC, an autosomal dominant
syndrome characterised by hamartoma formation in multiple organ
systems, cerebral calcifications, seizures and cognitive defects
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Sporadic LAM: 3.4 –7.5/million women
30-40% of patients with TSC (inc. 1: 6000 newborns)
• Often TSC patients diagnosed with LAM by screening are aymptomatic, have
mild disease by radiological criteria and exhibit normal lung function by
physiological testing
• TSC pts can also exhibit on chest radiographs noncalcified nodular lesions
characterized by Multifocal Micronodular Pneumocyte Hyperplasia (MMPH)
Exceptional in males
LAM - Prevalence
Costello LC et al, Mayo Clin Proc 2000
Moss J et al, AJRCCM 2001
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Multifocal Micronodular Pneumocyte Hyperplasia
(MMPH) Chest CT scan demonstrates multiple micronodules, present bilaterally in the
lung fields, independent of cystic changes.
Histologically, a proliferation
of type II pneumocytes,
without nuclear atypia
No immunoreactivity with
HMB45 as well as negative
results for estrogen and
progesterone receptors
Pathogenesis is probably
different from that of smooth cell muscle proliferation of LAM
The clinical significance in TSC pts is unknown; it does not appear to bepotentially fatal and differs in this respect to LAM
Franz, AJRCCM 2001
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Should be suspected in every young woman with a history of:
pneumothorax
chylothorax
angiomyolipoma
or the clinical finding of
“emphysema” in a non-smoker
LAM Diagnosis
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LAM is characterized by abnormal proliferation of LAM cells
In angiomyolipomas (AMLs) LAM cells are combined with dysplastic blood
vessels and adipocytes.
In the axial lymphatics, LAM cells form chaotic clumps of cells, leading to
thickening of lymphatic walls, obliteration of the vessel lumen and cystic
dilatation
Pathology of LAM lesions
Lung lesions are characterised
by lung nodules or small cell
clusters of LAM cells near cystic
lesions and along pulmonary
bronchioles, blood vessels and
lymphatics
Harari et al, ERR 2011
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Numerous thin-walled lung cysts distributed diffusely
throughout the lungs without sparing of lung bases
Radiological features - HRTC
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Thoracic manifestations
Most common:
- Dyspnea (over 70% of patients) is the result of airflow
obstruction, cystic destruction of the lung parenchyma and
pulmonary lymphatic congestion
- Pneumothorax (over 50% of patiens) is often the first manifestation
- Chylothorax
Others: Cough, chest pain, chyloptysis, hemoptysis
Chu SC et al, Chest 1999
Johnson SR et al, Thorax 2000
Taylor JR et al, NEJM 1990
Ryu JH et al, Chest 2003
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Extratoracic manifestationsAngiomyolipomas
AMLs are benign tumours that occur
in 80% of patients with TSC-LAM
and in 40% of those with S-LAM.
They may vary in size from 1 mm to
more than 20 cm in diameter, leading
to complete disruption of the normal
kidney architecture
In TSC, angiomyolipomas are larger,more frequently bilateral and moreprone to hemmorrhage
Bernstein SM et al, AJRCCM 1995
Maziak DE et al, ERJ 1996
Ryu JH et al, AJRCCM 2004
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Extratoracic manifestationsLymphangioleiomyomas
Associated symptoms are nausea, abdominal distension, peripheral
oedema and urinary symptoms.
Johnson SR et al, Thorax 2000
Avila NA et al, Radiology 2001
Lymphangioleiomyomas are large
cystic tumours primarily occuring
in the abdomen, retroperitoneum
and pelvis and can been found in
up to 10% of patients.
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The cystic lymphangioleiomyomas may change in sizeduring the day, perhaps due to the accumulation of fluid independent structures.
Morning and Afternoon Contrast-enhanced CT Scans of Pelvic Lymphangioleiomyomas
Morning Afternoon
Avila NA et al, Radiology 2001
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Chylous ascites due to lymphatic obstruction and associated with chylous thoracic effusions is present in 10% of patients with more advanced disease
Abdominal lymphadenopathy are found in 50% of patients
Extrathoracic manifestations
Avila NA et al, Radiology 2000
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Association of Sporadic LAM
and LAM/TSC with Meningiomas
Meningioma (3% of patients as found by MRI)
Meningiomas are biochemically, histologically and genetically similar to those found in the absence of LAM
Since the growth of meningiomas is enhanced by progesterone and growth factors, agents implicated in the pathogenesis of LAM, the increased frequency of meningiomas in LAM may, in some cases, result from these exogenous or endogenous factors.
Moss J et al, JAMA 2001
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characteristic lung HRCT + any of the following
- angiomyolipoma
- thoracic or abdominal chylous effusion,
- lymphangioleiomyoma
- biopsy-proven lymph node involved by LAM,
-TSC
characteristic lung HRTC + compatible clinical history
compatible lung HRTC + angiomyolipoma or chylous effusion
characteristic or compatible lung HRTC alone
Diagnosis – ERS guidelines
Characteristic HRCT: multiple (more than 10) thin-walled round well-defined air-filled cysts with no
other significant pulmonary involvement (with the exception of MMPY in TSC)
Compatible HRTC: few (more than two and fewer than 10) typical cysts
Johnson SR et al, ERJ 2010
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The diagnosis of LAM:
a role for BAL and TBB?
BAL
• No diagnostic relevance in LAM
• High percentage of pigment-laden macrophages likely due to microscopic pulmonary hemorrhages
TBB
• Higher diagnostic role than in PLCH
• Immunohistochemical staining (HMB-45) improves the diagnostic yield of TBB
Bonetti et al, Am J Surg Pathol 1993
Shan et al, Chest 1999
Harari S et al, Respir Med 2012
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Serum VEGF-D
McCormack FX, NEJM 2008
Serum vascolar endothelial growth factor levels have been shown to be higher in
pts with Lam than in healthy volunteers and pts with other pulmonary diseases
(histiocytosis, lymphangiomatosis, emphysema)
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Serum VEGF-D
Young LR et al, Chest 2010
A serum VEGF-D level of 800 pg/mL in a female with typical lung cystic
changes on HRCT scan has been proven to be diagnostically specific for S-
LAM and identifies LAM in females with TSC
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Serum VEGF-D concentration as a biomarker of
lymphangioleiomyomatosis severity and treatment response: a
prospective analysis of the Multicenter International
Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial
Young LR et al, Lancet Respir Med. 2013
Baseline VEGF-D concentrations correlated with baseline
markers of disease severity
Median serum VEGF-D concentrations fell from baseline at 6
and 12 months in the sirolimus group but remained roughly stable
in the placebo group
Each one-unit increase in baseline log(VEGF-D) was associated
with a between-group difference in baseline-to-12-month FEV1
change of 134 mL (p=0·0007)
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Crooks DM et al, PNAS 2004
LAM cells, identified by TSC2 LOH, have been isolated from the
blood and other body fluids of LAM patients
- Link between primary LAM lesions and the process that facilitates dispersion
of cells with metastatic potential
- The search for circulating LAM cells in blood or other fluid may identify
patients at risk of disease progression or spread and/or the response to potential
therapy.
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Proteins involved in extracellular matrix remodelling were
differentially expressed in LAM serum compared to control serum
A set of novel potential biomarkers?
Banville N et al, PLOS 2014
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St. George’s Respiratory Questionnaire in LAMData from MILES trial
Swigris JJ et al, Chest 2013
SGRQ scores are associated with variables used to assess
LAM severity, particularly FEV1
SGRQ can be capable of assessing longitudinal change
in impaired health-related quality of life in LAM
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LCH Smokers
Nodules in early disease
Basal sparing
Differential diagnosis
Birt Hogg Dube• Autosomal dominant defect in the folliculin gene
• Lung cysts, renal tumours and fibro-folliculomas
LIP
metastatic endometrial sarcoma
light chain deposition• patchy deposition of eosinophilic material in alveolar walls, small airways,
and vessels
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LAM: a neoplasm
Mutation
Inappropriate growth and survival
Metastasis via blood and lymphatic circulation
Infiltration
Tissue destruction
Sex steroid sensitivity
But the source of LAM cells is still unknown (Uterus? Angiomyolipomas?)
LAM cells show little evidence of proliferation
LAM pathogenic mechanisms mirror those of many forms of human
cancer
Henske1 EP and McCormack FX, J Clin Invest 2012
McCormack FX, et al. AJRCCM 2012
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LAM treatmentThe past: hormonal therapy
Oophorectomy
Anti-oestrogen therapy
Progesterone
Gonadotrophin-releasing hormone (GnRH) analogues
Controversial effects
No objective evidence
of improvement
Case reports
Retrospective studies
A prospective study showing no effects
on lung function
Case reports
Retrospective studies
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11 premenopausal LAM patients treated with triptorelin (11.25 mg IM
every 3 months); one withdrawal for drug side effects
Triptorelin was effective in suppressing ovarian function
No significant changes in lung function and in 6MWT
(all but 1 of the 10 patients who completed the study experienced a
decline in FEV1; a reduction in DLCO was observed in all patients)
Significant decline in bone mineral density
Effect of a Gonadotrophin-Releasing Hormone Analogue
on Lung Function in LAM
Harari S et al, Chest 2008
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Rheb
mTOR
S6K1 4E-BP1
TUBERINHAMARTIN
Translation
Cell growth
Cell proliferation
eIF4E
Sirolimus
Sirolimus is an immunosuppressant
currently in use for the prevention of
allograft rejection after solid organ
transplantation.
It inhibits the effect of mTORmediated
proliferation and growth of LAM cells in
vitro
AktThe main pathway involved in LAM
pathogenesis is mediated by Akt, whose
activation inhibits hamartin–tuberin complex,
leading to mammalian target of rapamycin
(mTOR) activation and thus to cell growth
and proliferation.
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In clinical trials sirolimus has been proved to
stabilize lung function, reduce serum VEGF-D
levels, decrease size of angiomyolipomas and
improve quality of life
LAM treatment
Bissler JJ et al, NEJM 2008
McCormack FX, NEJM 2011
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IIP
Sarc
BOOPLAM
HystPVD
Oth
87 Oth (31 vascul)
92 BOOP
103 LAM
47 Hx
129 PH
126 Sarc
495 IIP
(325 UIP)
Rare Lung diseasesOspedale San Giuseppe Experience (1999 - 2014)
Tot 1079 pts
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Our experience in LAM from 1999 to 2014
103 pts (18 TSC); an average of 7 new pts/year
Mean age (at diagnosis): 29.4 years
Mean redution FEV1 (whole population) - 94 ml/yr –
- in mTor treated pts mean reduction FEV1 -119 ml/yr before starting Tx
18 pts in post-menopausal age
31 pts with AMLs
Firs symptom at diagnosis Patients (n= 103)
Dyspnea 39
Pnx 33
Chylothorax 3
No symptom 28
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67 definite LAM:
- 31 suggestive HRCT + lung biopsy
- 10 suggestive HRCT + angiomyolipoma
- 11 suggestive HRCT + TSC
- 4 suggestive HRCT + involved lymph-nodes
- 3 suggestive HRCT + Chylotorax
- 8 suggestive HRCT + Lymphangioleiomyomas
33 probable LAM
- characteristic HRCT + compatible clinical history
3 possible LAM
- characteristic or compatible lung HRTC alone According to ERS LAM guidelines Eur Resp J, 2010
Our experience in LAM from 1999 to 2014
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PFTs at onset:
Bronchodilator testing 31ptsSalbutamol responders 7
Oxitropium responders 10
Our experience in LAM from 1999 to 2014
PFTs
PFTs at onset Patients, n 79 (%)
Obstructive 48 (61%)
Restrictive 1 (1.3%)
DlCO reduction 70 (87%)
Normal 35 (44%)
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Overall Survival in 100 LAM patients
Ospedale San Giuseppe experience 1999 – 2014 O
vera
ll S
urv
ival
0 2 4 6 8 10 12 14 16 18 20
0.0
0.2
0.4
0.6
0.8
1.0
100 87 75 46 36 29 23 16 11 8 5
Years
75%
33%
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LAM Follow-upOur experience
Evaluation at baseline:
- VEGF-D
- Lung function tests, Bronchodilator testing
- 6MWT
- Chest HRCT
- Blood gas measurement
- Clinical examination for TSC (if needed genetic screening)
- Abdomen CT or MRI when iodinated contrast is contraindicated
- Brain MRI
- Bone mineral density evaluation
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LAM Follow-upOur experience
Follow –up
- Lung function tests and 6MWT and Blood gas measurement every
3-6 months in patients with progressive disease and every 6-12
months in those with more stable disease
- VEGF-D every 3-6 months in patients with progressive disease or
mTOR inhibitor treatment
- Abdominal US every 6 -12 months in pts with AMLs
- Chest HRCT scan or abdominal CT or MRI if clinically indicated
- Bone mineral density evaluation every 18 months
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LAM treatmentOur experience
10 pts treated with triptorelin: all pts showed declining in lung function
8 pts treated with doxiciclin: all pts showed declining in lung function
30 pts treated with Sirolimus
- 3 improved at 12 months, 24 went stable, 3 pts showed worsening of lung function
( sirolimus blood level 5 - 15 ng/mL)
8 pts enrolled in RAD001X2201 trial (Everolimus), 1 withdrawal
due to hepatic toxicity – All stable after 24 moths
5 pts underwent lung transplantation
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Therapy with sirolimus: when?
Patients with severe lung function abnormalities
Asymptomatic patients who are declining rapidly
Symptomatic patients
Problematic chylous effusions
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Lung transplantation
LAM (inc. TSC-LAM) 1% of lung transplant recipients
Transplantation criteria - difficult due to clinical heterogeneity
• FEV1 25% & DLCO 27% at transplant
Referral
• NYHA grade III - IV, resting hypoxaemia
• Pleural surgery not a contraindication
Procedure
• bilateral may be preferred due to native lung complications
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Lung transplantation
outcomesThe European experience
- Total of 61 LTX
- Mean age at transplant 41.3 years (SD 5.1).
- 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.
- Recurrence of LAM occurred in 4 recipients.
- Kaplan–Meier survival was 79% at 1 year and 73% at 3
years post-transplant.Benden C et al, J Heart Lung Transplant.2009
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- Non invasive diagnosis of LAM is today possible
(ERS guidelines criteria -VEGF-D- circulating LAM cells
new biomarkers)
- LAM patients follow-up should be tailored according to
the severity of disease and to its progression
- mTor inhibitors are effective treatment for most patients
with more advanced disease or deteriorating
- For patients with respiratory failure lung transplantation is
a possible option with results similar to those observed for
other indications
Summary