Risk factors and prognostic analysis of lung cancer in combined pulmonary fibrosis and emphysema syndrome_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

ZENG Wenjing ¹ , FENG Xiaoyi ² ,  OU Xuemei ¹

1. Department of Pulmonary and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
2. Department of Respiratory and Critical Care Medicine, Peking Union Medical College and Peking Union Hospital, China Academy of Medical Sciences, Beijing 100730, P.R. China;

Corresponding?author：

OU Xuemei, Email: ouxuemeihx123@126.com

Keywords：

Combined pulmonary fibrosis and emphysema; clinical features; risk factors; prognosis; lung cancer

DOI：

10.7507/1671-6205.202504056

Video：

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Objective To systematically investigate the clinical characteristics, risk factors, and prognostic determinants of lung cancer (LC) in patients with combined pulmonary fibrosis and emphysema (CPFE). Methods A total of 180 CPFE patients admitted to West China Hospital of Sichuan University between December 2010 and December 2022 were collected in this retrospective study to explore the risk factors and prognosis of patients complicated with lung cancer. Results CPFE-LC predominantly occurs in elderly male smokers, with squamous cell carcinoma (33.33%) and adenocarcinoma (35.29%) being the most prevalent histological subtypes. Compared with CPFE patients, those with CPFE-LC demonstrated significantly higher proportions of males, current or former smokers, smoking index values, lymphocyte counts, neutrophil-to-lymphocyte ratios, serum albumin levels, fibrinogen levels, FEV₁%pred, and VC%pred. However, logistic regression analysis identified only male (OR=19.92, 95%CI 2.83-140.27) and elevated fibrinogen levels (OR=2.09, 95%CI 1.47-2.97) as independent risk factors for lung cancer development in CPFE patients. CPFE-LC patients exhibited significantly shorter survival than CPFE patients (1.67 years vs. 4.92 years, P<0.05). Kaplan-Meier survival analysis revealed no significant difference in survival among CPFE-LC patients with different histological subtypes (squamous cell carcinoma vs. adenocarcinoma vs. others, P>0.05). Conclusions Male and fibrinogen levels are independent risk factors for lung cancer development in patients with CPFE. Patients with CPFE-LC exhibited significantly shortened survival and poor prognosis. This unfavorable prognosis is closely associated with nutritional status, advanced tumor stage, metastasis status, and treatment modalities, but shows no significant association with histopathological type.

Citation： ZENG Wenjing, FENG Xiaoyi, OU Xuemei. Risk factors and prognostic analysis of lung cancer in combined pulmonary fibrosis and emphysema syndrome. Chinese Journal of Respiratory and Critical Care Medicine, 2025, 24(11): 797-806. doi: 10.7507/1671-6205.202504056 Copy

1.	Cottin V, Nunes H, Brillet PY, et al. Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity. Eur Respir J, 2005, 26(4): 586-593.
2.	Bolaki M, Antoniou KM. Combined Pulmonary Fibrosis and Emphysema. Semin Respir Crit Care Med, 2020, 41(2): 177-183.
3.	Gredic M, Karnati S, Ruppert C, et al. Combined Pulmonary Fibrosis and Emphysema: When Scylla and Charybdis Ally. Cells, 2023, 12(9): 1278.
4.	Chae KJ, Jin GY, Han YM, et al. Prevalence and progression of combined pulmonary fibrosis and emphysema in asymptomatic smokers: A case-control study. Eur Radiol, 2015, 25(8): 2326-2334.
5.	Li C, Wu W, Chen N, et al. Clinical characteristics and outcomes of lung cancer patients with combined pulmonary fibrosis and emphysema: a systematic review and meta-analysis of 13 studies. J Thorac Dis, 2017, 9(12): 5322-5334.
6.	Hage R, Gautschi F, Steinack C, et al. Combined Pulmonary Fibrosis and Emphysema (CPFE) Clinical Features and Management. Int J Chron Obstruct Pulmon Dis, 2021, 16: 167-177.
7.	Sugino K, Ishida F, Kikuchi N, et al. Comparison of clinical characteristics and prognostic factors of combined pulmonary fibrosis and emphysema versus idiopathic pulmonary fibrosis alone. Respirology, 2014, 19(2): 239-245.
8.	Wilson DO, Weissfeld JL, Balkan A, et al. Association of radiographic emphysema and airflow obstruction with lung cancer. Am J Respir Crit Care Med, 2008, 178(7): 738-744.
9.	Nasim F, Moua T. Lung cancer in combined pulmonary fibrosis and emphysema: a large retrospective cohort analysis. ERJ Open Res, 2020, 6(4): 00521-2020.
10.	Chen Q, Liu P, Zhou H, et al. An increased risk of lung cancer in combined pulmonary fibrosis and emphysema patients with usual interstitial pneumonia compared with patients with idiopathic pulmonary fibrosis alone: a systematic review and meta-analysis. Ther Adv Respir Dis, 2021, 15: 17534666211017050.
11.	Portillo K, Perez-Rodas N, García-Olivé I, et al. Lung cancer in patients with combined pulmonary fibrosis and emphysema and idiopathic pulmonary fibrosis. A descriptive study in a Spanish series. Arch Bronconeumol, 2017, 53(6): 304-310.
12.	Ikezoe K, Handa T, Tanizawa K, et al. The predictive risk factors for lung cancer in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med, 2018, 197: A1614.
13.	Kwak N, Park CM, Lee J, et al. Lung cancer risk among patients with combined pulmonary fibrosis and emphysema. Respiratory Medicine, 2014, 108(3): 524-530.
14.	Kawaguchi T, Koh Y, Ando M, et al. Prospective Analysis of Oncogenic Driver Mutations and Environmental Factors: Japan Molecular Epidemiology for Lung Cancer Study. J Clin Oncol, 2016, 34(19): 2247-2257.
15.	Feng X, Duan Y, Lv X, et al. The Impact of Lung Cancer in Patients with Combined Pulmonary Fibrosis and Emphysema (CPFE). JCM, 2023, 12(3): 1100.
16.	Raghu G, Remy-Jardin M, Richeldi L, et al. Idiopathic Pulmonary Fibrosis (an Update) and Progressive Pulmonary Fibrosis in Adults: An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med, 2022, 205(9): e18-e47.
17.	Zhang M, Yoshizawa A, Kawakami S, et al. The histological characteristics and clinical outcomes of lung cancer in patients with combined pulmonary fibrosis and emphysema. Cancer Med, 2016, 5(10): 2721-2730.
18.	Fujiwara A, Tsushima K, Sugiyama S, et al. Histological types and localizations of lung cancers in patients with combined pulmonary fibrosis and emphysema. Thorac Cancer, 2013, 4(4): 354-360.
19.	Gao L, Xie S, Liu H, et al. Lung cancer in patients with combined pulmonary fibrosis and emphysema revisited with the 2015 World Health Organization classification of lung tumors. Clin Respir J, 2018, 12(2): 652-658.
20.	Ballester B, Milara J, Cortijo J. Idiopathic Pulmonary Fibrosis and Lung Cancer: Mechanisms and Molecular Targets. Int J Mol Sci, 2019, 20(3): 593.
21.	Fava RA, Casey TT, Wilcox J, et al. Synthesis of transforming growth factor-beta 1 by megakaryocytes and its localization to megakaryocyte and platelet alpha-granules. Blood, 1990, 76(10): 1946-1955.
22.	Wang J, Sanmamed MF, Datar I, et al. Fibrinogen-like Protein 1 Is a Major Immune Inhibitory Ligand of LAG-3. Cell, 2019, 176(1-2): 334-347, e12.
23.	Sahni A, Francis CW. Vascular endothelial growth factor binds to fibrinogen and fibrin and stimulates endothelial cell proliferation. Blood, 2000, 96(12): 3772-3778.
24.	O'Byrne KJ, Koukourakis MI, Giatromanolaki A, et al. Vascular endothelial growth factor, platelet-derived endothelial cell growth factor and angiogenesis in non-small-cell lung cancer. Br J Cancer, 2000, 82(8): 1427-1432.
25.	Hohberger LA, Schroeder DR, Bartholmai BJ, et al. Correlation of regional emphysema and lung cancer: a lung tissue research consortium-based study. J Thorac Oncol, 2014, 9(5): 639-645.
26.	Chubachi S, Takahashi S, Tsutsumi A, et al. Radiologic features of precancerous areas of the lungs in chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis, 2017, 12: 1613-1624.
27.	Kawasaki H, Nagai K, Yoshida J, et al. Postoperative morbidity, mortality, and survival in lung cancer associated with idiopathic pulmonary fibrosis. J Surg Oncol, 2002, 81(1): 33-37.
28.	de Torres JP, Bastarrika G, Wisnivesky JP, et al. Assessing the relationship between lung cancer risk and emphysema detected on low-dose CT of the chest. Chest, 2007, 132(6): 1932-1938.
29.	Koo HJ, Do KH, Lee JB, et al. Lung Cancer in Combined Pulmonary Fibrosis and Emphysema: A Systematic Review and Meta-Analysis. PLOS One, 2016, 11(9): e0161437.

1. Cottin V, Nunes H, Brillet PY, et al. Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity. Eur Respir J, 2005, 26(4): 586-593.
2. Bolaki M, Antoniou KM. Combined Pulmonary Fibrosis and Emphysema. Semin Respir Crit Care Med, 2020, 41(2): 177-183.
3. Gredic M, Karnati S, Ruppert C, et al. Combined Pulmonary Fibrosis and Emphysema: When Scylla and Charybdis Ally. Cells, 2023, 12(9): 1278.
4. Chae KJ, Jin GY, Han YM, et al. Prevalence and progression of combined pulmonary fibrosis and emphysema in asymptomatic smokers: A case-control study. Eur Radiol, 2015, 25(8): 2326-2334.
5. Li C, Wu W, Chen N, et al. Clinical characteristics and outcomes of lung cancer patients with combined pulmonary fibrosis and emphysema: a systematic review and meta-analysis of 13 studies. J Thorac Dis, 2017, 9(12): 5322-5334.
6. Hage R, Gautschi F, Steinack C, et al. Combined Pulmonary Fibrosis and Emphysema (CPFE) Clinical Features and Management. Int J Chron Obstruct Pulmon Dis, 2021, 16: 167-177.
7. Sugino K, Ishida F, Kikuchi N, et al. Comparison of clinical characteristics and prognostic factors of combined pulmonary fibrosis and emphysema versus idiopathic pulmonary fibrosis alone. Respirology, 2014, 19(2): 239-245.
8. Wilson DO, Weissfeld JL, Balkan A, et al. Association of radiographic emphysema and airflow obstruction with lung cancer. Am J Respir Crit Care Med, 2008, 178(7): 738-744.
9. Nasim F, Moua T. Lung cancer in combined pulmonary fibrosis and emphysema: a large retrospective cohort analysis. ERJ Open Res, 2020, 6(4): 00521-2020.
10. Chen Q, Liu P, Zhou H, et al. An increased risk of lung cancer in combined pulmonary fibrosis and emphysema patients with usual interstitial pneumonia compared with patients with idiopathic pulmonary fibrosis alone: a systematic review and meta-analysis. Ther Adv Respir Dis, 2021, 15: 17534666211017050.
11. Portillo K, Perez-Rodas N, García-Olivé I, et al. Lung cancer in patients with combined pulmonary fibrosis and emphysema and idiopathic pulmonary fibrosis. A descriptive study in a Spanish series. Arch Bronconeumol, 2017, 53(6): 304-310.
12. Ikezoe K, Handa T, Tanizawa K, et al. The predictive risk factors for lung cancer in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med, 2018, 197: A1614.
13. Kwak N, Park CM, Lee J, et al. Lung cancer risk among patients with combined pulmonary fibrosis and emphysema. Respiratory Medicine, 2014, 108(3): 524-530.
14. Kawaguchi T, Koh Y, Ando M, et al. Prospective Analysis of Oncogenic Driver Mutations and Environmental Factors: Japan Molecular Epidemiology for Lung Cancer Study. J Clin Oncol, 2016, 34(19): 2247-2257.
15. Feng X, Duan Y, Lv X, et al. The Impact of Lung Cancer in Patients with Combined Pulmonary Fibrosis and Emphysema (CPFE). JCM, 2023, 12(3): 1100.
16. Raghu G, Remy-Jardin M, Richeldi L, et al. Idiopathic Pulmonary Fibrosis (an Update) and Progressive Pulmonary Fibrosis in Adults: An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med, 2022, 205(9): e18-e47.
17. Zhang M, Yoshizawa A, Kawakami S, et al. The histological characteristics and clinical outcomes of lung cancer in patients with combined pulmonary fibrosis and emphysema. Cancer Med, 2016, 5(10): 2721-2730.
18. Fujiwara A, Tsushima K, Sugiyama S, et al. Histological types and localizations of lung cancers in patients with combined pulmonary fibrosis and emphysema. Thorac Cancer, 2013, 4(4): 354-360.
19. Gao L, Xie S, Liu H, et al. Lung cancer in patients with combined pulmonary fibrosis and emphysema revisited with the 2015 World Health Organization classification of lung tumors. Clin Respir J, 2018, 12(2): 652-658.
20. Ballester B, Milara J, Cortijo J. Idiopathic Pulmonary Fibrosis and Lung Cancer: Mechanisms and Molecular Targets. Int J Mol Sci, 2019, 20(3): 593.
21. Fava RA, Casey TT, Wilcox J, et al. Synthesis of transforming growth factor-beta 1 by megakaryocytes and its localization to megakaryocyte and platelet alpha-granules. Blood, 1990, 76(10): 1946-1955.
22. Wang J, Sanmamed MF, Datar I, et al. Fibrinogen-like Protein 1 Is a Major Immune Inhibitory Ligand of LAG-3. Cell, 2019, 176(1-2): 334-347, e12.
23. Sahni A, Francis CW. Vascular endothelial growth factor binds to fibrinogen and fibrin and stimulates endothelial cell proliferation. Blood, 2000, 96(12): 3772-3778.
24. O'Byrne KJ, Koukourakis MI, Giatromanolaki A, et al. Vascular endothelial growth factor, platelet-derived endothelial cell growth factor and angiogenesis in non-small-cell lung cancer. Br J Cancer, 2000, 82(8): 1427-1432.
25. Hohberger LA, Schroeder DR, Bartholmai BJ, et al. Correlation of regional emphysema and lung cancer: a lung tissue research consortium-based study. J Thorac Oncol, 2014, 9(5): 639-645.
26. Chubachi S, Takahashi S, Tsutsumi A, et al. Radiologic features of precancerous areas of the lungs in chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis, 2017, 12: 1613-1624.
27. Kawasaki H, Nagai K, Yoshida J, et al. Postoperative morbidity, mortality, and survival in lung cancer associated with idiopathic pulmonary fibrosis. J Surg Oncol, 2002, 81(1): 33-37.
28. de Torres JP, Bastarrika G, Wisnivesky JP, et al. Assessing the relationship between lung cancer risk and emphysema detected on low-dose CT of the chest. Chest, 2007, 132(6): 1932-1938.
29. Koo HJ, Do KH, Lee JB, et al. Lung Cancer in Combined Pulmonary Fibrosis and Emphysema: A Systematic Review and Meta-Analysis. PLOS One, 2016, 11(9): e0161437.

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Risk factors and prognostic analysis of lung cancer in combined pulmonary fibrosis and emphysema syndrome

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