Radiologic Approach to Smoking Related Interstitial Lung Disease

Radiologic Approach to Smoking Related Interstitial Lung Disease Poster No.: C-1854 Congress: ECR 2013 Type: Educational Exhibit Authors: K.-N. Lee, J.-Y. Han, E.-J. Kang, J. Kang; Busan/KR Keywords: Toxicity, Computer Applications-General, Computer Applications-3D, CT-High Resolution, CT, Lung DOI: 10.1594/ecr2013/C-1854 Any information contained in this pdf file is automatically generated from digital material submitted to EPOS by third parties in the form of scientific presentations. References to any names, marks, products, or services of third parties or hypertext links to thirdparty sites or information are provided solely as a convenience to you and do not in any way constitute or imply ECR's endorsement, sponsorship or recommendation of the third party, information, product or service. ECR is not responsible for the content of these pages and does not make any representations regarding the content or accuracy of material in this file. As per copyright regulations, any unauthorised use of the material or parts thereof as well as commercial reproduction or multiple distribution by any traditional or electronically based reproduction/publication method ist strictly prohibited. You agree to defend, indemnify, and hold ECR harmless from and against any and all claims, damages, costs, and expenses, including attorneys' fees, arising from or related to your use of these pages. Please note: Links to movies, ppt slideshows and any other multimedia files are not available in the pdf version of presentations. www.myesr.org Page 1 of 17

Learning objectives 1. To review the pathophysiology of smoking related interstitial lung disease 2. To discuss and illustrate the CT features of Smoking related Interstitial lung disease Respiratory Bronchiolitis (RB) & RB - associated Interstitial Lung Disease Desquamative interstitial pneumonitis Pulmonary Langerhans cell histiocytosis Usual interstitial pneumonia (UIP or IPF) Combined Pulmonary Fibrosis and Emphysema Background Cigarette smoking is related to development of interstitial lung disease (ILD), such as respiratory bronchiolitis-interstitial lung disease (RB-ILD), desquamative interstitial lung disease (DIP), pulmonary Langerhan's cell histiocytosis (PLCH), idiopathic pulmonary fibrosis (IPF), and combined pulmonary fibrosis and emphysema (CPFE). Although the radiologic and histologic features overlap among these disease entities, distribution of lung nodules and cysts in a smoker can allow radiological differential diagnosis of smoking related ILD. The prognosis of smoking related ILD is variable according to the cessation or continuation of smoking. Imaging findings OR Procedure details 1. Respiratory Bronchiolitis (RB) & RB-associated Interstitial lung disease (ILD) RB ; Common histopathologic finding in smokers, which typically not associated with symptoms or functional deficit RB-ILD ; Symptomatic condition with radiologic and functional abnormalities Clinical presentation Page 2 of 17

Invariably middle aged smokers - Current smokers, Over 30 pack-year Dyspnea of insidious onset, cough - Less commonly chest pain, hemoptysis Bilateral inspiratory crackles Lung Function - RB ; no lung function deficit - RB-ILD ; mixed obstructive restrictive defect Pathophysiology RB Intraluminal and peribronchiolar airspace accumulation of pigmented macrophages Mild peribronchiolar mononuclear cell -> Fibroblast, collagen deposition -> Stellate fibrous scarring extending to alveolar wall RB-ILD Pronounced inflammation than in patient asymptomatic Patchy bronchiolocentric distribution HRCT of RB (Fig. 1 on page 9) Poorly defined centrilobular nodules 3-5mm Multifocal GGO Diffuse or Exclusively the upper lung zones Centrilobular emphysema HRCT of RB-ILD (Fig. 2 on page 9) Dominant GGO with centrilobular nodule "Image - Pathology Correlation" - Centrilobular nodules ; correlates with extent of macrophages in respiratory bronchioles and chronic respiratory bronchiolitis - GGO ; extent correlates with extent of macrophage accumulation in alveoli Page 3 of 17

- Bronchial wall thickening ; correlates with extent of alveolar macrophage 2. Desquamative Interstitial pneumonitis (DIP) Clinical presentation Rare condition, strongly linked with smoking (>90% are in smokers) Occasionally in dust exposure, drug reaction, leukemia 30-50s M:F=2:1 Insidious onset of dyspnea and nonproductive cough Restrictive defect, Diffusion capacity (DLCO) reduction Pathophysiology Similar, overlap between RB-ILD that there is pigmented macrophage accumulation in alveolar spaces End spectrum of RB-ILD - The only distinction ; More diffuse involvement of the air spaces Mild thickening of alveolar septa Mild honeycombing may occur Radiography (Fig. 3 on page 10) Bilateral basal hazy increased opacification with a reduction in lung volume Nonspecific reticular or reticulonodular pattern, with basal distribution HRCT (Fig. 4 on page 10, Fig. 5 on page 11, Fig. 6 on page 12) Presence of areas of GGO Subpleural and basal predominance Centrilobular emphysema Air-filled cysts may be visible within areas of GGO ; Dilated alveolar ducts and bronchioles, no honeycomb cysts Focal regions of lucency, representing airway obstruction Treatment and Outcome (Fig. 7 on page 12) Spontaneous improvement may occur Prognosis improved with stop smoking Steroid unclear Roughly 25% of cases worsen despite treatment with steroid Page 4 of 17

3. Pulmonary Langerhans Cell Histiocytosis (PLCH) Synonyms; Histiocytosis X, Eosinophilic granuloma, Langerhans cell granulomatosis Simplified division; Single-organ or multiorgan involvement Pulmonary Langerhans cell histiocytosis usually occurs in isolation, but also found in most adult cases with multisystem disorder Clinical presentation Young or middle-aged adults Cough dyspnea, fever, malaise, chest pain, asymptomatic, rare hemoptysis 10-16% present with pneumothorax Younger in pts with pneumothorax, 60% are recurrent Multiorgan ; pituitary, skin, eye, colon, heart, LNs, brain - most common site is lung PFT : Reduction in diffusion capacity (DLCO) Mixed restrictive, obstructive pulmonary function in advanced disease Pathophysiology Smoke Antigen -> Macrophage activation and cytokine production -> Langerhans cell recruitment, T cell expansion -> Inflammation Agents produced by macrophage -> collagen, fibroblast proliferation Cellular infiltrate centered around the membranous bronchioles - DIP-like reaction (pigmented macrophage infiltrating airspace) Cystic spaces result from destruction of the bronchiolar wall and progressive enlargement of the airway lumen "ball valve" effect End-stage ; replaced by fibrosis, cystic spaces, pulmonary vascular involvement, pulmonary hypertension HRCT ( Fig. 8 on page 13, Fig. 9 on page 13, Fig. 10 on page 13 ) Bronchiolocentric ill-defined nodules (1-5mm) - Profuse, predominate in upper, mid lung - Sparing of cardiophrenic angle, lingula, RML Bizarrely shaped cysts - Distribution same with nodules - Walls ranging from thin and barely perceptible to several millimeters in thickness - Billobed, cloverleaf shaped, branching in appearance - Eccentric with coalescence in more advanced disease GGO, Fine reticulation, air trapping "Image - Pathology Correlation" Page 5 of 17

- Centrilobular nodules ; florid granuloma formation - Cysts ; cavitary granulomas, cysts with fibrous walls - GGO ; presence of RB, DIP Treatment and Prognosis Treatment - Smoking cessation leads to stabilization of symptoms - Steroids, chemotherapeutic agents Prognosis - Compared to multisystem disease, isolated pulmonary involvement is better - Regresses spontaneously in 25% - Stabilized clinically and radiologically in 50% - Progressive downhill course, resulting in diffuse cystic lung destruction in 25% 4. Idiopathic Pulmonary Fibrosis (IPF) Clinical manifestation High prevalence of current or former smokers in series of IPF, varying from 41-83% Smoking as a risk factor for IPF 1.58 6th-7th decade of life Progressing dyspnea, chronic cough, bibasilar inspiratory crackles, digital clubbing Diagnostic criteria Major Page 6 of 17

1.Exclusion of known causes of ILD, such as exposures, drugs, connective tissue disease 2.PFT ; restriction and impaired gas exchange 3.HRCT of bibasilar reticulation with minimal GGO 4.Transbronchial lung Bx or BAL showing no other ds Minor 1.Age>50 2.Insidious onset of dyspnea on exertion 3.Duration of illness of >3months 4.Bibasilar dry crackles (velcrolike) HRCT ( Fig. 11 on page 14 ) Findings of fibrosis - Honeycombing - Traction bronchiectasis and bronchiolectasis - Intralobular interstitial thickening > irregular interlobular septal thickening GGO in areas showing fibrosis ; active inflammation Distribution - Peripheral and subpleural predominance - Lower lung zone and posterior predominance - Patchy distribution ; areas of mild, severe fibrosis, inflammatory activity, normal lung present in same lung, same lobe 5. Combined Pulmonary Fibrosis and Emphysema (CPFE) Clinical manifestation Increasingly recognized as distinct entity in smokers 6th-7th decades Relatively preserved lung volumes Severe reduction in diffusion capacity High prevalence of pulmonary HTN HRCT ( Fig. 12 on page 14 ) Page 7 of 17

Emphysema in the upper lungs and fibrosis in lower lungs - Emphysema and fibrosis may co-occur in the same area Emphysematous foci may have apparent walls due to thickening of the adjacent interlobular septa Pattern of Usual interstial pneumonia (UIP) : usual findings - Pattern of Nonspecific interstitial pneumonia (NSIP), RB-ILD, or DIP Differential diagnosis of cystic lesions with additional informations 1. Extensive nodules - Sarcoidosis, Silicosis, Metastasis : perilymphatic - LCH, Lymphoid interstitial pneumonia (LIP) : centrilobular 2. Different distributions - UIP ; Honeycombing subpleral lung regions, bases - Lymphangioleiomyomatosis (LAM) ; Lower 1/3 lung involved, uniform distribution - Centrilobular emphysema ; Upper lobe predominance, lack visible walls - LIP ; Lower lobe cysts 3. Clinical history and additional findings - LIP ; Underlying autoimmune disease, Interlobular septal thickening, GGO, nodules - DIP with emphysema; Findings of patchy GGO - LAM ; Tuberous sclerosis, rarely occurs in men, rare nodules Page 8 of 17

Images for this section: Fig. 1: RB in a 35-year-old man with a 10 pack-year history of smoking who had no respiratory symptoms. HRCT image (a) obtained through the upper lungs shows bilateral faint centrilobular ground-glass nodules (GGO). HRCT image with coronal reformatted image (b) shows centrinodular GGOs predominantly distributed in both upper lung. Fig. 2: RB-ILD in a 67-year-old man with a 40 pack-year history of smoking who presented with dyspnea on exertion for 10 days and restriction at pulmonary function Page 9 of 17

testing, with FEV1/FVC 54%. HRCT image with coronal reformatted image (a) and obtained through the upper lungs (b) shows bilateral centrilobular GGOs with upper lung predominance. HRCT image obtained through the lower lungs (c) shows geographic areas of GGO in right basal lung. HRCT obtained at the same level of (d-e) show marked improvement after 4 months of oral corticosteroid with smoking cessation. Fig. 3 Page 10 of 17

Fig. 4: Early DIP in a 70-year-old smoker. Areas of GGO are present with basal predominence. Note air-filled cysts are visible within areas of GGO and are different from honeycombing cysts. Fig. 5: A 62-year-old man who has desquamative interstitial pneumonia. (a) HRCT at the level of the aortic arch shows diffuse ground-glass opacity with multiple cysts in variable size. Some subpleural cysts are difficult to differentiate from paraseptal emphysema. (b) HRCT obtained at the lower level shows that ground-glass attenuation in a peripheral and patchy distribution predominantly in the lower lung zones. Page 11 of 17

Fig. 6: DIP and emphysema in a 65-year-old heavy smoker who presented with gradually increasing shortness of breath. (a) HRCT image obtained through the upper lungs shows bilateral paraseptal emphysema. (b-c) Middle and lower lungs show subplueral and basal GGO and small cysts (arrow). Page 12 of 17

Fig. 7: Follow up images of patient in Figure 6. (d-e) HRCT obtained after 3 years show a marked increase in GGO and reticulation. The size of peripheral lung cysts are bigger compared with previous exams (f-g) After 3 month-period of steroid treatment, peripheral GGO resolved, while the lung cysts remained. Fig. 8: PLCH in a 49-year-old woman with a 60 pack-year history of smoking (a-c) HRCT images show bilateral irregular morphology of cysts in an upper lung predominance. Note a relative sparing of basal lung in (c). There are also irregular cavitating nodules (arrows) which are on the process of changing to thin walled cyst. Fig. 9: PLCH with multiorgan involvement in a 36-year-old male smoker with back pain. HRCT with coronal reformatted image (a) shows irregular cysts and reticular opacities in both upper lungs, simulating emphysema. Skull radiograph (b) and CT images (bone window, c) show multifocal lucent lesions in the skull, right rib and vertebral body. Page 13 of 17

Fig. 10: Pulmonary LCH in a 23-year-old woman. (a) High resolution CT scans (lung window) show irregular and bizarrely shaped cysts. (b) Note some cysts have relatively thick wall (arrows) compared to other cysts with imperceptable wall. Fig. 11: Advanced IPF in a 64-year-old former smoker with exertional dyspnea for an year. (a) HRCT image shows reticulation and multifocal areas of traction bronchiectasis with subpleural distribution. (b) CT image obtained through lower lungs shows extensive honeycombing. Page 14 of 17

Fig. 12: CPFE in a 65-year-old male smoker with chronic cough. (a) HRCT image obtained through the upper lungs shows paraseptal and centrilobular emphysema. (b) HRCT image obtained through the lower lungs shows peripheral honeycombing and reticulation (arrow). (c) Coronal reformatted image shows the upper lung apical distribution of the emphysema and the lower lung distribution of the fibrosis. Page 15 of 17

Conclusion We illustrate the diagnostic approach to patients with smoking related ILD, which leads early diagnosis. However, we emphasize the importance reviewing of all the clinical readiologic and pathologic information to make final diagnosis of specific entity. Summary Age RB-ILD DIP PLCH UIP CPFE 30-40s 30-50s 20-40s 50-60s 50-60s Subpleural, Basal C-P angle, Peripheral, RML spared Subpleural Upper (emphysema), Lower (fibrosis) - Distribution Upper Nodule Centrilobular - Centrilobular, cavitary Cyst - Within the areas of GGO Bizarrely shaped HoneycombingHoneycombing Emphysema +/- +/- - - Possible additional findings GGO, Reticulation GGO, Traction Pattern of Reticulation, bronchiectasis,uip Air trapping Septal thickening GGO + References 1. Attili AK, Kazerooni EA, Gross BH, et al. Smoking-related Interstitial Lung Disease:Radiologic-Clinical-Pathologic Correlation. RadioGraphics 28:1383-1398 2008; 2. Abbott GF, Rosado-de-Christenson ML, Franks TJ, et al. Pulmonary Langerhans Cell Histiocytosis. RadioGraphics 2004; 24:821-841 Page 16 of 17

3. Mang CM, Grosse C, Schmid K, et al. What Every Radiologist Should Know about Idiopathic Interstitial Pneumonias. RadioGraphics 2007; 27: 595-615 4. Ryu JH, Colby TV, Hartman TE, et al. Smoking related interstitial lung diseases: a concise review. Eur Respir J 2001; 17: 122-132 5. Heyneman LE, Ward S, Lynch DA, et al. Respiratory Bronchiolitis, Respiratory Bronchiolitis-Associated Interstitial Lung Disease, and Desquamative Interstitial Pneumonia: Different Entities or Part of the Spectrum of the Same Disease Process?. Am J Roentgenol 1999; 173: 1617-1622 6. Vassallo R, Ryu JH, Colby TV, et al. Pulmonary Langerhans'-Cell HistiocytosisN Engl J Med 2000; 342: 1969-1978 7. Tazi A. Adult pulmonary Langerhans' cell histiocytosis. Eur Respir J 2006; 27: 1272-1285 8. Galvin JR, Franks TJ. Smoking-related Lung Disease. Proc Am Thorac Soc 2006; 3: 299-306 9. Vassallo R, Jensen EA, Colby TV, et al. The Overlap Between Respiratory Bronchiolitis and Desquamative Interstitial Pneumonia in Pulmonary Langerhans Cell HistiocytosisChest 2003; 124: 1199-1205 Personal Information Page 17 of 17