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

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?

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

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

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

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

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

Numerous thin-walled lung cysts distributed diffusely

throughout the lungs without sparing of lung bases

Radiological features - HRTC

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

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

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.

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

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

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

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

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

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)

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

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)

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.

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

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

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

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

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

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

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.

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

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

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

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

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%)

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%

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

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

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

Therapy with sirolimus: when?

Patients with severe lung function abnormalities

Asymptomatic patients who are declining rapidly

Symptomatic patients

Problematic chylous effusions

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

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

- 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