Bassel Ericsoussi, MD Pulmonary and Critical Care Fellow University of Illinois at Chicago

Pulmonary Langerhans Cell Histiocytosis (PLCH) Eosinophilic Granuloma of the Lung Pulmonary Langerhans Cell Granulomatosis Pulmonary Histiocytosis X Uncommon ILD Young adults Caucasians Equal gender distribution Smoke is an etiologic factor The duration of illness is usually less than one year prior to diagnosis

Pulmonary Langerhans Cell Histiocytosis (PLCH)

Eosinophilic Granuloma of the Lung

Pulmonary Langerhans Cell Granulomatosis

Pulmonary Histiocytosis X

Uncommon ILD

Young adults

Caucasians

Equal gender distribution

Smoke is an etiologic factor

The duration of illness is usually less than one year prior to diagnosis

Langerhans cells: PLCH (cluster of Langerhans cells ) Smokers IPF Bronchioloalveolar carcinoma Early inflammatory lesions surround the bronchioles, pulmonary arterioles and venules Intraluminal fibrosis with progression to interstitial fibrosis (occur with advanced disease) Predominance of disease in the mid to upper zones of the lung (IPF: lower zone predominance )

Langerhans cells:

PLCH (cluster of Langerhans cells )

Smokers

IPF

Bronchioloalveolar carcinoma

Early inflammatory lesions surround the bronchioles, pulmonary arterioles and venules

Intraluminal fibrosis with progression to interstitial fibrosis (occur with advanced disease)

Predominance of disease in the mid to upper zones of the lung (IPF: lower zone predominance )

Early lesions appear as cellular infiltrates Vascular intimal fibrosis with luminal obliteration (arrow) in a region involved by interstitial fibrosis and chronic inflammation

Strong association with cigarette smoking No association of smoking with extrapulmonary Langerhans cell histiocytosis Generalized activation or abnormalities in immune function Increase in IgG in BAL Immune complexes in the circulation Abnormalities in T-cell function

Strong association with cigarette smoking

No association of smoking with extrapulmonary Langerhans cell histiocytosis

Generalized activation or abnormalities in immune function

Increase in IgG in BAL

Immune complexes in the circulation

Abnormalities in T-cell function

Present to medical attention Incidental findings on CXR Spontaneous pneumothorax Respiratory or constitutional symptoms: Nonproductive cough (56 to 70 %) Dyspnea (40 to 87 %) Pleuritic chest pain (10 to 21 %) Fatigue (30 %) Weight loss (20 to 30 %) Fever (15 %)

Present to medical attention

Incidental findings on CXR

Spontaneous pneumothorax

Respiratory or constitutional symptoms:

Nonproductive cough (56 to 70 %)

Dyspnea (40 to 87 %)

Pleuritic chest pain (10 to 21 %)

Fatigue (30 %)

Weight loss (20 to 30 %)

Fever (15 %)

Usually unremarkable Fine crackles and digital clubbing LABORATORY STUDIES Usually unrevealing Eosinophil count is normal

Usually unremarkable

Fine crackles and digital clubbing

LABORATORY STUDIES

Usually unrevealing

Eosinophil count is normal

Recurrent spontaneous pneumothorax (15 to 25%)that may cause pleural thickening or effusion Pulmonary arteriopathy and veno-occlusive disease independent from parenchymal and airway disease Impair diffusing capacity and exercise capacity (out of proportion to imaging findings) Pulmonary hypertension Severe Common (88 % by echocardiogram) a/w increased mortality Hemoptysis (13 %) Tumors (strong a/w smoking) - precede, follow, or occur concomitantly Bronchogenic carcinoma (5 %) Hodgkin's and non-Hodgkin's lymphoma [ Pulmonary carcinoid tumor Mediastinal ganglioneuroma.

Recurrent spontaneous pneumothorax (15 to 25%)that may cause pleural thickening or effusion

Pulmonary arteriopathy and veno-occlusive disease independent from parenchymal and airway disease

Impair diffusing capacity and exercise capacity (out of proportion to imaging findings)

Pulmonary hypertension

Severe

Common (88 % by echocardiogram)

a/w increased mortality

Hemoptysis (13 %)

Tumors (strong a/w smoking) - precede, follow, or occur concomitantly

Bronchogenic carcinoma (5 %)

Hodgkin's and non-Hodgkin's lymphoma [

Pulmonary carcinoid tumor

Mediastinal ganglioneuroma.

Cystic bone lesions (4 to 20 %) localized pain or a pathologic bone fracture Diabetes insipidus (hypothalamic involvement) 15 % Worse prognosis.

Cystic bone lesions (4 to 20 %)

localized pain or a pathologic bone fracture

Diabetes insipidus (hypothalamic involvement)

15 %

Worse prognosis.

Symptoms are nonspecific h/o recurrent pneumothorax, diabetes insipidus, or bone pain can be helpful Current or past smoking history

Symptoms are nonspecific

h/o recurrent pneumothorax, diabetes insipidus, or bone pain can be helpful

Current or past smoking history

CXR Ill-defined nodules Reticulonodular infiltrates (middle, upper lung zones ) Preservation of lung volume (hyperinflation and reduced volume can occur ) Costophrenic angle sparing

CXR

Ill-defined nodules

Reticulonodular infiltrates (middle, upper lung zones )

Preservation of lung volume (hyperinflation and reduced volume can occur )

Costophrenic angle sparing

HRCT: progression from nodules to cavitating nodules to cystic lesions Multiple cysts and nodules (mid to upper zones) Interstitial thickening Honeycombing

HRCT: progression from nodules to cavitating nodules to cystic lesions

Multiple cysts and nodules (mid to upper zones)

Interstitial thickening

Honeycombing

Restrictive pattern Out of proportion reduction in DLCO Pulmonary arteriopathy and veno-occlusive disease Minority of patients (more advanced, cystic disease) may have hyperinflation with reactive airways sometimes may benefit from bronchodilator

Restrictive pattern

Out of proportion reduction in DLCO

Pulmonary arteriopathy and veno-occlusive disease

Minority of patients (more advanced, cystic disease) may have hyperinflation with reactive airways

sometimes may benefit from bronchodilator

Limitation in activity and exercise intolerance out of proportion to pulmonary function abnormalities and imaging studies Pathologic involvement of the pulmonary vasculature Pulmonary arteriopathy and veno-occlusive disease independent from parenchymal and airway disease Alveolar-arterial oxygen gradient Normal at rest Increased in exercise

Limitation in activity and exercise intolerance out of proportion to pulmonary function abnormalities and imaging studies

Pathologic involvement of the pulmonary vasculature

Pulmonary arteriopathy and veno-occlusive disease independent from parenchymal and airway disease

Alveolar-arterial oxygen gradient

Normal at rest

Increased in exercise

Strongly suggests the diagnosis > 5 % Langerhans cells on BAL Langerhans cells can be seen Smokers IPF Bronchioloalveolar carcinoma

Strongly suggests the diagnosis

> 5 % Langerhans cells on BAL

Langerhans cells can be seen

Smokers

IPF

Bronchioloalveolar carcinoma

Transbronchial biopsy Usually is sufficient to make the diagnosis Contraindicated in severe PAH (common in PLCH) Video thoracoscopic lung biopsy Langerhans cells Characteristic staining for S-100 protein Immunostaining with CD1a Extensive fibrosis and less Langerhans cells in progressive disease

Transbronchial biopsy

Usually is sufficient to make the diagnosis

Contraindicated in severe PAH (common in PLCH)

Video thoracoscopic lung biopsy

Langerhans cells

Characteristic staining for S-100 protein

Immunostaining with CD1a

Extensive fibrosis and less Langerhans cells in progressive disease

Cessation of smoking Immunosuppressive therapies (steroids, cytotoxics) are of limited value Palliative radiotherapy for symptomatic bone lesions Lung transplantation In advanced, progressive disease (severe pulmonary hypertension in end-stage PLCH) Recurrence in the transplanted lung 20 % Good postransplant survival rate

Cessation of smoking

Immunosuppressive therapies (steroids, cytotoxics) are of limited value

Palliative radiotherapy for symptomatic bone lesions

Lung transplantation

In advanced, progressive disease (severe pulmonary hypertension in end-stage PLCH)

Recurrence in the transplanted lung 20 %

Good postransplant survival rate

The natural history Progression to end-stage fibrotic lung disease (with continued cigarette smoking) Spontaneous remission of symptoms (with the cessation of smoking ) Good prognostic factors Smoking Cessation Sparing of the costophrenic angle Poor prognostic factors Pulmonary hypertension (increased mortality) Diabetes insipidus (hypothalamic involvement) Cigarettes smoking Involvement of the costophrenic angle

The natural history

Progression to end-stage fibrotic lung disease (with continued cigarette smoking)

Spontaneous remission of symptoms (with the cessation of smoking )

Good prognostic factors

Smoking Cessation

Sparing of the costophrenic angle

Poor prognostic factors

Pulmonary hypertension (increased mortality)

Diabetes insipidus (hypothalamic involvement)

Cigarettes smoking

Involvement of the costophrenic angle

5 yrs survival 74%

Video thoracoscopic lung biopsy to make the diagnosis of PLCH (transbronchial biopsy is contraindicated in severe PH) Echocardiogram should be done to all PLCH dyspneic pts to diagnose PH Diminished exercise capacity in PLCH is related to pulmonary vascular dysfunction (not to ventilatory limitation) PH in PLCH is related to pulmonary circulation involvement independent of small airway and lung parenchyma injury Pulmonary arteriopathy and veno-occlusive disease Recurrence in the transplanted lung 20 %

Video thoracoscopic lung biopsy to make the diagnosis of PLCH (transbronchial biopsy is contraindicated in severe PH)

Echocardiogram should be done to all PLCH dyspneic pts to diagnose PH

Diminished exercise capacity in PLCH is related to pulmonary vascular dysfunction (not to ventilatory limitation)

PH in PLCH is related to pulmonary circulation involvement independent of small airway and lung parenchyma injury

Pulmonary arteriopathy and veno-occlusive disease

Recurrence in the transplanted lung 20 %

Histiocytosis Association of America: www.histio.org/us/assn Pulmonary Langerhans cell histiocytosis: www.uptodate.com Dauriat G, Mal H, Thabut G, Mornex JF, Bertocchi M, Tronc F, Leroy-Ladurie F, Dartevelle P, Reynaud-Gaubert M, Thomas P, Pison C, Blin D, Stern M, Bonnette P, Dromer C, Velly JF, Brugière O, Lesèche G, Fournier M. Lung transplantation for pulmonary langerhans' cell histiocytosis: a multicenter analysis. Transplantation. 2006 Mar 15;81(5):746-50. Chaowalit N, Pellikka PA, Decker PA, Aubry MC, Krowka MJ, Ryu JH, Vassallo R. Echocardiographic and clinical characteristics of pulmonary hypertension complicating pulmonary Langerhans cell histiocytosis. Mayo Clin Proc. 2004 Oct;79(10):1269-75. Harari S, Comel A. Pulmonary Langerhans cell Histiocytosis. Sarcoidosis Vasc Diffuse Lung Dis. 2001 Oct;18(3):253-62. Hamada K, Teramoto S, Narita N, Yamada E, Teramoto K, Kobzik L. Pulmonary veno-occlusive disease in pulmonary Langerhans' cell granulomatosis. Eur Respir J. 2000 Feb;15(2):421-3. Fartoukh M, Humbert M, Capron F, Maître S, Parent F, Le Gall C, Sitbon O, Hervé P, Duroux P, Simonneau G. Severe pulmonary hypertension in histiocytosis X. Am J Respir Crit Care Med. 2000 Jan;161(1):216-23 Crausman RS, King TE Jr. Pulmonary vascular involvement in pulmonary histiocytosis X. Chest. 1997 Dec;112(6):1714 Harari S, Brenot F, Barberis M, Simmoneau G. Advanced pulmonary histiocytosis X is associated with severe pulmonary hypertension. Chest. 1997 Apr;111(4):1142-4

Histiocytosis Association of America: www.histio.org/us/assn

Pulmonary Langerhans cell histiocytosis: www.uptodate.com

Dauriat G, Mal H, Thabut G, Mornex JF, Bertocchi M, Tronc F, Leroy-Ladurie F, Dartevelle P, Reynaud-Gaubert M, Thomas P, Pison C, Blin D, Stern M, Bonnette P, Dromer C, Velly JF, Brugière O, Lesèche G, Fournier M. Lung transplantation for pulmonary langerhans' cell histiocytosis: a multicenter analysis. Transplantation. 2006 Mar 15;81(5):746-50.

Chaowalit N, Pellikka PA, Decker PA, Aubry MC, Krowka MJ, Ryu JH, Vassallo R. Echocardiographic and clinical characteristics of pulmonary hypertension complicating pulmonary Langerhans cell histiocytosis. Mayo Clin Proc. 2004 Oct;79(10):1269-75.

Harari S, Comel A. Pulmonary Langerhans cell Histiocytosis. Sarcoidosis Vasc Diffuse Lung Dis. 2001 Oct;18(3):253-62.

Hamada K, Teramoto S, Narita N, Yamada E, Teramoto K, Kobzik L. Pulmonary veno-occlusive disease in pulmonary Langerhans' cell granulomatosis. Eur Respir J. 2000 Feb;15(2):421-3.

Fartoukh M, Humbert M, Capron F, Maître S, Parent F, Le Gall C, Sitbon O, Hervé P, Duroux P, Simonneau G. Severe pulmonary hypertension in histiocytosis X. Am J Respir Crit Care Med. 2000 Jan;161(1):216-23

Crausman RS, King TE Jr. Pulmonary vascular involvement in pulmonary histiocytosis X. Chest. 1997 Dec;112(6):1714

Harari S, Brenot F, Barberis M, Simmoneau G. Advanced pulmonary histiocytosis X is associated with severe pulmonary hypertension. Chest. 1997 Apr;111(4):1142-4