1. Interval History The patient was admitted to respiratory isolation to rule out active infection with Mycobacterium Tuberculosis Acid-fast bacilli culture and smear were negative The patient improved on empiric NSAIDs and was discharged home The patient returned to her baseline exercise tolerance and was asymptomatic within 1 week

2. Interval History Repeat CT imaging showed resolution of effusions, but persistent nodules, concerning for metastatic disease of unknown primary PET Scan and Abdominal CT scans did not show evidence of extrapulmonary malignancy The patient returned two months later for a thorascopy with lung wedge resection of a characteristic nodule

3. 4x

4. 10x

5. 20x

6. 40x

7. CD1a

8. S100

9. PULMONARY LANGERHANS’- CELL HYSTIOCYTOSIS Final Pathological Diagnosis

10. PLCH: Introduction Histiocytosis encompasses a group of diverse disorders with the common primary event of the accumulation and infiltration of monocytes, macrophages, and dendritic cells in the affected tissues Langerhans Cells are a dendritic cell subtype and part of the monocyte- macrophage lineage derived from bone marrow involved in antigen presentation in the tracheobronchial tree

11. Classification of Histiocytosis Single-organ involvement o Lung (>85% of lung involvement occurs in isolation) o Bone o Skin o Pituitary o Lymph Nodes o Thyroid, Liver, Spleen, Brain Multisystem Disease o Multiorgan disease with lung involvement o Multiorgan disease without lung involvement o Multiorgan histiocytic disorder

12. Historical Terms Hystiocytosis X Eosinophilic Granuloma Letter-Siwe disease o A rare systemic aggressive disease seen in adults Hand-Schüller-Christian disease o Triad of exopthalmos, central diabetes insipidus, and bone lesions

13. Langerhans Cells Discovered by Paul Langerhans in 1868 The hallmark ultrastructural feature called the Birbeck Granule discovered in 1961 The CD1a cell surface antigen distinguises LC from other histiocytes

14. Epidemiology Precise incidence and prevalence is hard to define in this disease o 1200 new cases per year o 0.5-5.4 cases / million 5% of lung-biopsy specimens in patients with ILD result in PLCH No known genetic susceptibility Mainly in caucasians. Male to female ratio is changing over the decades… >90% of PLCH patients are smokers

15. Vassallo R et al. N Engl J Med 2000;342:1969-1978 Proposed Pathogenesis of PLCH

16. Reactive vs. Neoplastic? Spontaneous remission Abscence of chromosomal abnormalities Overall good prognosis in majority of cases Monoclonal proliferation in extrapulmonary tissue Infiltration of aberrent cells into normal tissue Response to chemotherapy and possible fatal outcome in more severe cases

17. Histopathological Features Proliferation of Lagerhans Cells along the small airways serves as the nidus of cellular/fibrotic nodules from 5mm to 1.5 in size. Eosinophils may be present In severe disease, nodules may interconnect and cavitate to produce distinctive honeycomb-like structures Given that most patients are smokers, concominant COPD and ILD 2/2 respiratory bronchiolitis is often present

18. Clinical Presentation Cough (50-70%) Dyspnea (30-50%) Fever, weight loss, diaphoresis (20- 30%) Asymptomatic (25%) Chest Pain (10%)

19. Clinical Presentation Pneumothorax (10-20%) Extrapulmonary disease (15%) Pulmonary hypertension Respiratory failure Secondary malignancy Physical Exam and Laboratory findings are variable

20. Chest Radiography Symmetrical micronodular and Interstitial infiltration predominantly in the middle and upper lobes Increased lung volumes Rare: alveolar infiltrates, hilar LAD, pleural effusion

22. Tissue Diagnosis Bronchoalveolar Lavage Transbronchial Biopsy Open vs. Thorascopic Lung Biopsy

24. Management Smoking Cessation Corticosteroids Chemotherapy o Vinblastine, MTX, Cyclophosphamide, Etoposide o 2-chlorodeoxyadenosine Immune modulation: Etanercept Pleurodesis of pneumothoraces Serial TTE and PFTs to monitor progression

25. Prognosis For a majority of patients, the disease regresses with smoking cessation It is not known to predict those who tend to progress, although age, prolonged constitutional symptoms, extrapulmonary involvement, abnormal PFTs are markers of poor outcome

26. Back to our case… This patient has baseline respiratory insufficiency 2/2 PLCH and COPD, but presented with an acute respiratory illness not characteristic of these diagnoses She endorsed chills, dyspnea, and chest pain. There was radiographic evidence of pleuropericarditis which symptomatically and radiographically improved within 1-2 weeks on NSAIDs

27. Dfdx of pleuropericarditis Viral / Acute idiopathic Drug-induced Collagen vascular: Sarcoid, RF, Lupus Tuberculosis Malignancy Infarction pericarditis Uremia Atypical infections: fungal

28. Follow-up Pleural fluid was negative for Acid-Fast, Bacterial or Fungal organisms HIV Negative The patient continues to struggle with smoking cessation and reports baseline shortness of breath and cough The patient reports an increase in smoking because of the anxiety of “having cancer” Steroids have not been offerred due to the relatively mild course of her disease

29. Dfdx of pleuropericarditis Viral / Acute idiopathic Drug-induced Collagen vascular: Sarcoid, RF, Lupus Tuberculosis Malignancy Infarction pericarditis Uremia Atypical infections: fungal

30. Dfdx of pleuropericarditis Viral / Acute Idiopathic Drug-induced Collagen vascular: Sarcoid, RF, Lupus Tuberculosis Malignancy Infarction pericarditis Uremia Atypical infections: fungal

31. Final Diagnoses Pulmonary Langerhans’-Cell Histiocytosis, Acute Viral Plueropericarditis Active Tobacco Abuse Coronary Artery Disease COPD Essential HTN Anxiety / Dysthymia

32. Active Tobacco Abuse COPD HTN CADPLCH Age Diminished epithelial defenses and mucociliary elevator Viral respiratory pathogen? Pleuropericarditis Chronic respiratory insufficiency, cough and exercise intolerance Acute self-limited dyspnea and atypical chest pain Increased cough, Subjective chills CPC 9.12.08 Flowsheet Acute phase reactants: Platelets, Ferritin, ESR Dysthymia/Anxiety Chronic illness: Anemia of chronic disease and low albumin

33. Thank You! Dr. Martin Blaser Dr. Anthony Grieco Dr. Elvio Ardilles Dr. Jonathon Ralston Dr. Kristin Remus Dr. James Tsay Dr. Christina Yoon