1. CA 19-9 in Patients with Pulmonary Fibrosis Department of Rheumatology Doohyun Woo

2. INTRODUCTION  Tumor markers  in serum are helpful in cancer diagnosis  in BALF is useful in diagnosing lung cancer that is not visible endoscopically  Some tumor markers  elevated s-levels in some benign lung or non-pulmonary diseases, healthy smokers, and systemic diseases  elevated BALF in smokers and non-malignant lung diseases

3. Harrison 16 th Table 66-5 Cecil 22 nd Table 189-1 Colorectal CEA Ovary CA12-5 Breast CA15-3, CA27.29 Prostate PSA Testicle hCG, AFP Hepatoma AFP Myeloma ß 2 -microglobulin NHL LDH Tumor marker Tumor marker CancerNon-Neoplastic Conditions CA19-9 CEA Adenocarcinomas of colon Pancreas, lung, breast, ovary Pancreatitis, hepatitis, IBD, smoking Colon, Pancreatic, breast cancer Pancreatitis, ulcerative colitis

4.  CA19-9  Marker of pancreatic and biliary cancer  Bronchiolar epithelial cells in pulmonary diseases such as IPF, diffuse panbronchiolitis and tuberculosis  Chemotactic activity for neutrophils  Carcinoembryonic antigen (CEA)  Typically associated with malignant epithelial neoplasm  Can present at elevated levels even in normal individuals and interstitial lung diseases  How CA19-9, CEA affect the pathogenesis of IPF is not known

5.   Yoshitaka et al. Rispiration 2001;68:438 JOURNAL  Serum CA19-9 levels ☞ positive correlation with extent of disease on chest X-ray, severity of dyspnea on exertion & BALF neutrophil levels ☞ Did not correlate with markers of disease activity (serum LDH, KL-6, SP-A, SP-D levels, intensity of chest Ga scan)  BALF CA19-9 levels ☞ exhibited a positive correlation with BALF neutrophil levels ☞ were positively correlated with serum CA19-9 levels ☞ Purified CA19-9 has a neutrophil chemotactic feature → Serum CA19-9 levels may represent the progression of lung fibrosis, but not disease activity → CA19-9 is considered to be mainly produced by lung tissues CA19-9 may induce neutrophil accumulation in lung tissues

6.  Mukae et al.  Immunohistochemical study of pts with lung fibrosis ☞ CA19-9 is expressed in bronchiolar epithelial cells & regenerating epithelial cells of fibrosing alveolar septi  CA19-9 are secreted from bronchial gland apically into the lumen  Increases in neutrophil in BALF & lung tissue in IPF Nippon Kyobu Shikkan Zasshi 1999;29:611-617 In IPF, persistent epithelial cell damage & neutrophils accumulation in lower respiratory tract may cause high levels of CA19-9 in BALF

7. Non-significant Relatively increased in IPF significant chemotactic activity for neutrophils at concentrations of 10– 1,000 U/ml Rispiration 2000;67:146-152  Yuka Obayashi et al. CA19-9 can modify neutrophil functions Role of BALF CA19-9 in IPF

8. BALF CA19-9 significantly correlated with HGF Elastase LDH Alveolar macrophages Neutrophils CA19-9 in BALF correlated with other markers of inflammation in IPF  CA19-9 may play a role in the process of lung injury in patients with pulmonary fibrosis

9. CEA in bronchoalveolar lavage fluid in IPF. Takahashi H et al., Jpn J Med.1985 Aug;24(3):236-43 % of high CEA level in BALF. 25% smoker control, 44% nonsmoker with IPF, 62% smoker with IPF, 75% smoker with IPF & lung cancer, 81% primary lung cancer Increase of CEA in BALF is a possible marker of early histological disorders in the lung, and also suggests a greater risk of malignant change in the clinical course of IPF. CEA and CA19-9 in BALF in idiopathic interstitial pneumonia (IIP) Shiota Y et al., Nihon Kyobu Shikkan Gakkai Zasshi. 1989 Aug;27(8):887-93 CEA and CA19-9 in the BALF were significantly higher in IIP than healthy subjects and significant correlations with BALF neutrophil in IIP. Immunohistochemical study, CEA staining in the epithelia of respiratory bronchioles and alveoli CA19-9 staining in the epithelia of the respiratory bronchioles but not of alveoli. CEA in BALF may be useful to estimate degree of pathological change & activity of IIP.

10. Marked elevation of CA19-9 in IPF: CA19-9 as a bad prognostic factor. Fujita J et al., Respirology. 1998 Sep;3(3):211-4 We also reviewed the Index Medics and picked up the cases who had elevation of CA19-9 more than 1000 U/mL, six patients were listed. Five of these six patients died within 6 months, therefore the marked elevation of CA19-9 seemed to be a bad prognostic factor in patients with pulmonary fibrosis. Clinical characterization of CA19-9 in interstitial pneumonia Totani Y et al., Nihon Kokyuki Gakkai Zasshi. 2005 Feb;43(2):77-83 Serum levels of CA19-9 did not correlate with serum LDH, of KL-6, or of SP-D or chest Ga-67 scan. Immunohistochemistry of CA19-9 showed the strong positivity in bronchiolar epitheliums located in severe fibrotic lesions and mucus within microscopic honeycomb. Serum levels of CA19-9 may reflect the progression of lung fibrosis but not the disease activity in interstitial pneumonia.

11. CONCLUSIONS  Serum CA19-9 levels in pulmonary fibrosis  is considered to be mainly produced by lung tissues  might play the role of a neutrophil chemoattractant  may reflect BALF neutrophil levels  may represent disease progression, but not disease activity  marked elevation of CA19-9 seemed to be a bad prognostic factor  BALF CA19-9 correlated with other markers of inflammation  BALF CEA levels in pulmonary fibrosis  possible marker of early histological disorders in the lung  suggests a greater risk of malignant change in the clinical course of IPF

12. CASE F/39 F/39 내원 1 년전 RA 진단 내원 1 년전 RA 진단 2 개월 전부터 dyspnea 발생 2 개월 전부터 dyspnea 발생 Interstitial pneumonitis 진단받고 Interstitial pneumonitis 진단받고 cyclophosphamide pulse Tx. cyclophosphamide pulse Tx.  HRCT 변화 ?  HRCT 변화 ?

13. AB post #7