IgG4-RELATED LUNG DISEASE. Erik Baltaxe Institute of Pulmonary Diseases Chaim Sheba Medical Center

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1 IgG4-RELATED LUNG DISEASE Erik Baltaxe Institute of Pulmonary Diseases Chaim Sheba Medical Center

2 Case Presentations Case Age / Sex Initial Presentation Associated Conditions 1 44 / F Cough, shortness of breath Dry eyes (d/t dacryoadenitis) 2 21 / M Productive cough, pleuritic chest pain Asthma 3 58 / M Pleural thickening incidental CT finding Retroperitoneal fibrosis, mesenteric panniculitis, aortitis

3 Case Radiology Pathology Clinical Cases Summary Serum IgG4 (mg/dl) 1 Multifocal bilateral alveolar infiltrates. Peribronchovascular infiltrates * Core needle biopsy (lung). * Thickened interstitium with lymphoplasmocytic infiltrate. * Obliterative phlebitis. * IgG4 + cells / HPF. * No granulomas Right upper lobe solid mass (3 cm) with spiculated margins * RU Lobectomy * Lymphoplasmocytic infiltration. * No vasculitis. * 20 25% IgG4 + cells. * Ratio of IgG4/IgG + cells: 20-25% Right pleural thickening including the anterior mediastinum, with calcified lesions. * Core needle biopsy. * Densely fibrotic paucicellular pleura. * Lung parenchyma with dense lymphoplasmocytic infiltrate. * IgG4 negative. * No asbestos bodies or silica particles. 177

4 Case FEV1 (%) FVC (%) FRC (%) TLC (%) DLCO (%)

5 Stone JH et al. N Engl J Med 2012;366:

6 Physiology and Pathogenesis Elevations in serum and tissue IgG4 also found in multicentric Castleman s disease allergic disorders Churg-Strauss syndrome lung cancer sarcoidosis

7 Clinical Presentation (hepatobiliary) Zen Y., et al. IgG4-Related Disease. A Cross-sectional Study of 114 Cases. Am J Surg Pathol. 2010:

8 Clinical Presentation Single and multiorgan involvement. Subacute development of a mass in the affected organ. Multiple organs in %. Lymphadenopathy is common Symptoms of asthma or allergy in 40%. Absence of fever or other constitutional symptoms. Incidental finding (radiology or histology).

9 Previously Recognized Conditions Now Acknowledged to Fall within the Spectrum of IgG4-Related Disease Stone JH et al. N Engl J Med 2012;366:

10 Clinical Presentation Cough, effort dyspnea and chest pain in 50%. 3 reported cases with constitutional symptoms and elevated inflammatory markers. 50% asymptomatic with incidental findings on chest radiology. Zen Y, et al. IgG4-related lung and pleural disease: a clinicopathologic study of 21 cases. Am J Surg Pathol Inoue D, et al. Immunoglobulin G4-related lung disease: CT findings with pathologic correlations. Radiology Sun X, et al. Refractory IgG4-related Lung Disease with Constitutional Symptoms and Severe Inflammation. AJRCCM. 2014

11 Radiological Features Inoue D el al. (2009) described 4 patterns: Solid nodular Round-shaped ground-glass opacity Alveolar interstitial (honeycombing, bronchiectasis and diffuse GGO). Bronchovascular Ryu JH el al. (2012) described mediastinal lymphadenopathy. Yamashita K, et al. (2008) and Sekiguchi H, et al. (2012) described pleural involvement.

12 Radiological Features Solid Nodular (Case #2)

13 Radiological Features Round-shaped ground-glass Opacity Inoue D, et al. Immunoglobulin G4-related lung disease: CT findings with pathologic correlations. Radiology. 2009

14 Radiological Features Alveolar Interstitial (honeycombing, bronchiectasis and diffuse GGO) Inoue D, et al. Immunoglobulin G4-related lung disease: CT findings with pathologic correlations. Radiology. 2009

15 Radiological Features Bronchovascular (Case #1) Inoue D, et al. Radiology. 2009

16 Radiological Features Mediastinal Lymphadenopathy (Case #1) Ryu JH, et al.. Eur Resp J. 2012

17 Radiological Features Pleural Thickening (Case #3)

18 Radiological Features Inoue D, et al. Immunoglobulin G4-related lung disease: CT findings with pathologic correlations. Radiology. 2009

19 Pathology Key histopathological findings: Dense lymphoplasmocytic infiltrate Storiform-type fibrosis Obliterative phlebitis Mild-to-moderate eosinophilic infiltration Fibrosis may predominate in the late phases. Differential diagnosis with lymphomas. The presence of granulomas generally excludes the diagnosis of IgG4-related disease. Prominent neutrophilic infiltrate is inconsistent with the diagnosis.

20 Pathology Lung pathology is characterized by: Nonspecific Interstitial Pneumonia (NSIP) pattern. Irregular fibrosis in the nodular and pleural lesions. Obliterative phlebitis. Eosinophilic infiltration. Zen Y, et al. IgG4-related lung and pleural disease: a clinicopathologic study of 21 cases. Am J Surg Pathol. 2009

21 Diagnosis Consensus statement on the pathology of IgG4-related disease. Modern Pathology Histologically Highly Suggestive of IgG4-Related Disease At last two of the following: Dense lymphoplasmacytic infiltrate Fibrosis, usually storiform in character Obliterative phlebitis. IgG4+ plasma cell counts differ between organs and type of sample: Core needle biopsy: > 20 cells / hpf Lung surgical specimen: > 50 cells / hpf

22 Diagnosis Probable Histological Features of IgG4-Related Disease Cases with only a single histopathological feature Meningeal and cutaneous disease Needle biopsies These cases require additional evidence to confirm the diagnosis of IgG4-related disease, such as: Serum IgG4 > 135 mg/dl. Other organ involvement, as demonstrated by radiological or pathological examination. Insufficient Histopathological Evidence of IgG4- Related Disease Sampling artifact, the effects of previous therapy, and progression to a fibrotic stage.

23 Diagnosis IgG4 levels are increased in BAL fluid. These levels were observed to correlate with the serum IgG4 level. Bronchoalveolar lavage data relating to IgG4-related pulmonary disease are sparse and its role in the evaluation of patients remains to be clarified. Tsushima K, et al. Pulmonary involvement of autoimmune pancreatitis. Eur J Clin Invest

24 Treatment Oral Steroids Favorable response usually observed within 2 wks. In a series of 4 cases Khosroshahi A et al. (2010) showed a rapid decline of serum IgG4 levels after Rituximab treatment.

25 Prognosis Long-term follow up data has not been published. Extrathoracic lesions in follow-up: months to years. Persistent radiological abnormalities. 3/21 patients is Zen el al. series (2009) Association with lymphoma, pancreatic cancer and lung cancer. 2/21 of lung cancer in Zen el al. series (2009) Increased risk of malignancy? Progression to fibrosis in untreated cases. Poor response to steroids when fibrosis is established.

26 Conclusions IgG4-related disease is a poorly understood inflammatory condition. Systemic disease. Thoracic disease can involve the lung parenchyma, airways, mediastinum and pleura. Diagnosis is based on histology and serum IgG4 levels. Good response to steroid therapy. Uncertain relationship with malignancy.

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