Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter July 4, 2022

Diagnostic utility of pleural cell-free nucleic acids in undiagnosed pleural effusions

  • Wen Zhao , Xi-Shan Cao , Yu-Ling Han , Xu-Hui Wen , Wen-Qi Zheng and Zhi-De Hu ORCID logo EMAIL logo

Abstract

Pleural effusion (PE) is a common sign caused by various disorders. Microbiology, histology and cytology are reference standards for these disorders. However, these diagnostic tools have limitations, including invasiveness, high cost, long turnaround time, and observer-dependent. Soluble biomarkers in pleural fluid (PF) are promising diagnostic tools because they are mininvasive, economical, and objective. Recent studies have revealed that some cell-free nucleic acids (e.g., DNA, mRNA, microRNA, and lncRNA) in PF are potential diagnostic markers for many disorders. Here, we review the performance of PF cell-free nucleic acids for differentiating and stratification of PE.


Corresponding author: Zhi-De Hu, PhD, Department of Laboratory Medicine, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010010, P.R. China, E-mail:

Award Identifier / Grant number: 81860501

  1. Research funding: This work was supported by the National Natural Science Foundation of China (81860501).

  2. Author contributions: Zhi-De Hu designed and supervised the study. Wen Zhao collected the data from previous studies and drafted the manuscript. Xi-Shan Cao, Yu-Ling Han, and Xu-Hui Wen provided administrative support and provided intellectual contributions to the manuscript. Zhi-De Hu and Wen-Qi Zheng critically reviewed and edited the manuscript. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: The authors have no conflicts of interest to declare.

  4. Conflict of interest: Not applicable.

  5. Ethical approval: Not applicable.

References

1. Tian, P, Qiu, R, Wang, M, Xu, S, Cao, L, Yang, P, et al.. Prevalence, causes, and health care burden of pleural effusions among hospitalized adults in China. JAMA Netw Open 2021;4:e2120306. https://doi.org/10.1001/jamanetworkopen.2021.20306.Search in Google Scholar PubMed PubMed Central

2. Zhang, M, Li, D, Hu, ZD, Huang, YL. The diagnostic utility of pleural markers for tuberculosis pleural effusion. Ann Transl Med 2020;8:607. https://doi.org/10.21037/atm.2019.09.110.Search in Google Scholar PubMed PubMed Central

3. Sehgal, IS, Dhooria, S, Aggarwal, AN, Behera, D, Agarwal, R. Diagnostic performance of xpert MTB/RIF in tuberculous pleural effusion: systematic review and meta-analysis. J Clin Microbiol 2016;54:1133–6. https://doi.org/10.1128/jcm.03205-15.Search in Google Scholar

4. Bielsa, S, Acosta, C, Pardina, M, Civit, C, Porcel, JM. Tuberculous pleural effusion: clinical characteristics of 320 patients. Arch Bronconeumol 2019;55:17–22. https://doi.org/10.1016/j.arbr.2018.11.006.Search in Google Scholar

5. Arnold, DT, De Fonseka, D, Perry, S, Morley, A, Harvey, JE, Medford, A, et al.. Investigating unilateral pleural effusions: the role of cytology. Eur Respir J 2018;52:1801254. https://doi.org/10.1183/13993003.01254-2018.Search in Google Scholar PubMed

6. Maskell, NA, Batt, S, Hedley, EL, Davies, CW, Gillespie, SH, Davies, RJ. The bacteriology of pleural infection by genetic and standard methods and its mortality significance. Am J Respir Crit Care Med 2006;174:817–23. https://doi.org/10.1164/rccm.200601-074oc.Search in Google Scholar PubMed

7. Wang, XJ, Yang, Y, Wang, Z, Xu, LL, Wu, YB, Zhang, J, et al.. Efficacy and safety of diagnostic thoracoscopy in undiagnosed pleural effusions. Respiration 2015;90:251–5. https://doi.org/10.1159/000435962.Search in Google Scholar PubMed

8. Avasarala, SK, Lentz, RJ, Maldonado, F. Medical thoracoscopy. Clin Chest Med 2021;42:751–66. https://doi.org/10.1016/j.ccm.2021.08.010.Search in Google Scholar PubMed

9. Liang, QL, Shi, HZ, Wang, K, Qin, SM, Qin, XJ. Diagnostic accuracy of adenosine deaminase in tuberculous pleurisy: a meta-analysis. Respir Med 2008;102:744–54. https://doi.org/10.1016/j.rmed.2007.12.007.Search in Google Scholar PubMed

10. Porcel, JM. Biomarkers in the diagnosis of pleural diseases: a 2018 update. Ther Adv Respir Dis 2018;12:1753466618808660. https://doi.org/10.1177/1753466618808660.Search in Google Scholar PubMed PubMed Central

11. Cortez, MA, Bueso-Ramos, C, Ferdin, J, Lopez-Berestein, G, Sood, AK, Calin, GA. MicroRNAs in body fluids--the mix of hormones and biomarkers. Nat Rev Clin Oncol 2011;8:467–77. https://doi.org/10.1038/nrclinonc.2011.76.Search in Google Scholar PubMed PubMed Central

12. Ponti, G, Manfredini, M, Tomasi, A. Non-blood sources of cell-free DNA for cancer molecular profiling in clinical pathology and oncology. Crit Rev Oncol-Hematol 2019;141:36–42. https://doi.org/10.1016/j.critrevonc.2019.06.005.Search in Google Scholar PubMed

13. Porcel, JM, Vives, M, Vicente de Vera, MC, Cao, G, Rubio, M, Rivas, MC. Useful tests on pleural fluid that distinguish transudates from exudates. Ann Clin Biochem 2001;38:671–5. https://doi.org/10.1258/0004563011901082.Search in Google Scholar PubMed

14. Gonlugur, U, Gonlugur, TE. The distinction between transudates and exudates. J Biomed Sci 2005;12:985–90. https://doi.org/10.1007/s11373-005-9014-1.Search in Google Scholar PubMed

15. Chan, MH, Chow, KM, Chan, AT, Leung, CB, Chan, LY, Chow, KC, et al.. Quantitative analysis of pleural fluid cell-free DNA as a tool for the classification of pleural effusions. Clin Chem 2003;49:740–5. https://doi.org/10.1373/49.5.740.Search in Google Scholar PubMed

16. Carpagnano, GE, Costantino, E, Palladino, GP, Lacedonia, D, Martinelli, D, Orlando, S, et al.. Microsatellite alterations and cell-free DNA analysis: could they increase the cytology sensitivity in the diagnosis of malignant pleural effusion? Rejuvenation Res 2012;15:265–73. https://doi.org/10.1089/rej.2011.1260.Search in Google Scholar PubMed

17. Porcel, JM, Sorolla, A, Parisi, E, Bielsa, S, Salud, A, Sorolla, MA. Cell-free DNA concentration and pattern fragmentation in pleural fluid and plasma to detect malignant effusions. Ann Am Thorac Soc 2022;19:854–6. https://doi.org/10.1513/annalsats.202107-810rl.Search in Google Scholar

18. Santotoribio, JD, Cabrera-Alarcon, JL, Batalha-Caetano, P, Macher, HC, Guerrero, JM. Pleural fluid cell-free DNA in parapneumonic pleural effusion. Clin Biochem 2015;48:1003–5. https://doi.org/10.1016/j.clinbiochem.2015.07.096.Search in Google Scholar PubMed

19. Su, CM, Kung, CT, Hsiao, SY, Tsai, NW, Lai, YR, Huang, CC, et al.. Diagnosis of parapneumonia pleural effusion with serum and pleural fluid cell-free DNA. BioMed Res Int 2019;2019:5028512. https://doi.org/10.1155/2019/5028512.Search in Google Scholar PubMed PubMed Central

20. Heffner, JE, Brown, LK, Barbieri, C, DeLeo, JM. Pleural fluid chemical analysis in parapneumonic effusions. A meta-analysis. Am J Respir Crit Care Med 1995;151:1700–8. https://doi.org/10.1164/ajrccm.151.6.7767510.Search in Google Scholar PubMed

21. Bao, QL, Li, J, Sun, W, Jiang, HG, Zhu, LR, Wang, Y. Diagnostic utility of LUNX mRNA and VEGF mRNA in pleural fluid for differentiating benign from malignant origin. Jpn J Clin Oncol 2014;44:1198–205. https://doi.org/10.1093/jjco/hyu141.Search in Google Scholar PubMed

22. Sun, W, Li, J, Jiang, HG, Ge, LP, Wang, Y. Diagnostic value of MUC1 and EpCAM mRNA as tumor markers in differentiating benign from malignant pleural effusion. QJM 2014;107:1001–7. https://doi.org/10.1093/qjmed/hcu130.Search in Google Scholar PubMed

23. Wang, L, Liu, B, Wang, T, Ding, Y, Qian, X, Zhao, Y. Detection of cell-free ERCC1 and thymidylate synthase (TS) mRNA in malignant effusions and its association with anticancer drug sensitivity. Anticancer Res 2008;28:1085–91.Search in Google Scholar

24. Lv, M, Mou, Y, Wang, P, Chen, Y, Wang, T, Hou, Y. Diagnostic and predictive role of cell-free midkine in malignant pleural effusions. J Cancer Res Clin Oncol 2013;139:543–9. https://doi.org/10.1007/s00432-012-1359-z.Search in Google Scholar PubMed

25. Berezikov, E, Guryev, V, van de Belt, J, Wienholds, E, Plasterk, RH, Cuppen, E. Phylogenetic shadowing and computational identification of human microRNA genes. Cell 2005;120:21–4. https://doi.org/10.1016/j.cell.2004.12.031.Search in Google Scholar PubMed

26. Yang, Y, Ma, L, Qiao, X, Zhang, X, Dong, SF, Wu, MT, et al.. Salivary microRNAs show potential as biomarkers for early diagnosis of malignant pleural effusion. Transl Lung Cancer Res 2020;9:1247–57. https://doi.org/10.21037/tlcr-19-530.Search in Google Scholar PubMed PubMed Central

27. Zhu, LR, Yuan, RX, Xia, XB, Wang, Y, Zhu, YM, Fi, L, et al.. Assessment of a panel of miRNAs in serum and pleural fluid for the differential diagnosis of malignant and benign pleural effusion. Cancer Biomarkers 2022;33:71–82. https://doi.org/10.3233/cbm-210090.Search in Google Scholar PubMed

28. Xie, L, Chen, X, Wang, L, Qian, X, Wang, T, Wei, J, et al.. Cell-free miRNAs may indicate diagnosis and docetaxel sensitivity of tumor cells in malignant effusions. BMC Cancer 2010;10:591. https://doi.org/10.1186/1471-2407-10-591.Search in Google Scholar PubMed PubMed Central

29. Xie, L, Wang, T, Yu, S, Chen, X, Wang, L, Qian, X, et al.. Cell-free miR-24 and miR-30d, potential diagnostic biomarkers in malignant effusions. Clin Biochem 2011;44:216–20. https://doi.org/10.1016/j.clinbiochem.2010.11.002.Search in Google Scholar PubMed

30. Liu, C, Huang, L, Zhang, X, Yang, J. Combination of DNA ploidy analysis and miR-21 or miR-24 in screening malignant pleural effusion. Interact Cardiovasc Thorac Surg 2018;26:376–81. https://doi.org/10.1093/icvts/ivx327.Search in Google Scholar PubMed

31. Shin, YM, Yun, J, Lee, OJ, Han, HS, Lim, SN, An, JY, et al.. Diagnostic value of circulating extracellular miR-134, miR-185, and miR-22 levels in lung adenocarcinoma-associated malignant pleural effusion. Cancer Res Treat 2014;46:178–85. https://doi.org/10.4143/crt.2014.46.2.178.Search in Google Scholar PubMed PubMed Central

32. Huang, L. The expression and clinical significance of B7-H3 and miR-145 in lung cancer patients with malignant pleural effusion. Eur Rev Med Pharmacol Sci 2020;24:6759–66.Search in Google Scholar

33. Han, HS, Yun, J, Lim, SN, Han, JH, Lee, KH, Kim, ST, et al.. Downregulation of cell-free miR-198 as a diagnostic biomarker for lung adenocarcinoma-associated malignant pleural effusion. Int J Cancer 2013;133:645–52. https://doi.org/10.1002/ijc.28054.Search in Google Scholar PubMed

34. Bao, Q, Xu, Y, Ding, M, Chen, P. Identification of differentially expressed miRNAs in differentiating benign from malignant pleural effusion. Hereditas 2020;157:6. https://doi.org/10.1186/s41065-020-00119-z.Search in Google Scholar PubMed PubMed Central

35. Bianco, A, Valente, T, De Rimini, ML, Sica, G, Fiorelli, A. Clinical diagnosis of malignant pleural mesothelioma. J Thorac Dis 2018;10:S253–61. https://doi.org/10.21037/jtd.2017.10.09.Search in Google Scholar PubMed PubMed Central

36. Birnie, KA, Prêle, CM, Musk, AWB, de Klerk, N, Lee, YCG, Fitzgerald, D, et al.. MicroRNA signatures in malignant pleural mesothelioma effusions. Dis Markers 2019;2019:8628612. https://doi.org/10.1155/2019/8628612.Search in Google Scholar PubMed PubMed Central

37. Zhang, L, Zhou, Q, Han, YQ, Li, P, Ouyang, PH, Wang, MY, et al.. Diagnostic accuracy of circulating miR-126 for malignant pleural mesothelioma: a systematic review and meta-analysis. Transl Cancer Res 2021;10:1856–62. https://doi.org/10.21037/tcr-21-104.Search in Google Scholar PubMed PubMed Central

38. Han, YQ, Xu, SC, Zheng, WQ, Hu, ZD. Diagnostic value of microRNAs for malignant pleural mesothelioma: a mini-review. Thorac Cancer 2021;12:8–12. https://doi.org/10.1111/1759-7714.13746.Search in Google Scholar PubMed PubMed Central

39. Wang, T, Lv, M, Shen, S, Zhou, S, Wang, P, Chen, Y, et al.. Cell-free microRNA expression profiles in malignant effusion associated with patient survival in non-small cell lung cancer. PLoS One 2012;7:e43268. https://doi.org/10.1371/journal.pone.0043268.Search in Google Scholar PubMed PubMed Central

40. Han, HS, Jo, YN, Lee, JY, Choi, SY, Jeong, Y, Yun, J, et al.. Identification of suitable reference genes for the relative quantification of microRNAs in pleural effusion. Oncol Lett 2014;8:1889–95. https://doi.org/10.3892/ol.2014.2404.Search in Google Scholar PubMed PubMed Central

41. Kalluri, R, LeBleu, VS. The biology, function, and biomedical applications of exosomes. Science 2020;367. https://doi.org/10.1126/science.aau6977.Search in Google Scholar PubMed PubMed Central

42. Becker, A, Thakur, BK, Weiss, JM, Kim, HS, Peinado, H, Lyden, D. Extracellular vesicles in cancer: cell-to-cell mediators of metastasis. Cancer Cell 2016;30:836–48. https://doi.org/10.1016/j.ccell.2016.10.009.Search in Google Scholar PubMed PubMed Central

43. Rabinowits, G, Gerçel-Taylor, C, Day, JM, Taylor, DD, Kloecker, GH. Exosomal microRNA: a diagnostic marker for lung cancer. Clin Lung Cancer 2009;10:42–6. https://doi.org/10.3816/clc.2009.n.006.Search in Google Scholar

44. Lin, J, Wang, Y, Zou, YQ, Chen, X, Huang, B, Liu, J, et al.. Differential miRNA expression in pleural effusions derived from extracellular vesicles of patients with lung cancer, pulmonary tuberculosis, or pneumonia. Tumour Biol 2016;37:15835–45. https://doi.org/10.1007/s13277-016-5410-6.Search in Google Scholar PubMed

45. Wang, Y, Xu, YM, Zou, YQ, Lin, J, Huang, B, Liu, J, et al.. Identification of differential expressed PE exosomal miRNA in lung adenocarcinoma, tuberculosis, and other benign lesions. Medicine (Baltim) 2017;96:e8361. https://doi.org/10.1097/md.0000000000008361.Search in Google Scholar PubMed PubMed Central

46. Hydbring, P, De Petris, L, Zhang, Y, Brandén, E, Koyi, H, Novak, M, et al.. Exosomal RNA-profiling of pleural effusions identifies adenocarcinoma patients through elevated miR-200 and LCN2 expression. Lung Cancer 2018;124:45–52. https://doi.org/10.1016/j.lungcan.2018.07.018.Search in Google Scholar PubMed

47. Ulivi, P, Zoli, W. miRNAs as non-invasive biomarkers for lung cancer diagnosis. Molecules 2014;19:8220–37. https://doi.org/10.3390/molecules19068220.Search in Google Scholar PubMed PubMed Central

48. Tamiya, H, Mitani, A, Saito, A, Ishimori, T, Saito, M, Isago, H, et al.. Exosomal microRNA expression profiling in patients with lung adenocarcinoma-associated malignant pleural effusion. Anticancer Res 2018;38:6707–14. https://doi.org/10.21873/anticanres.13039.Search in Google Scholar PubMed

49. Iyer, MK, Niknafs, YS, Malik, R, Singhal, U, Sahu, A, Hosono, Y, et al.. The landscape of long noncoding RNAs in the human transcriptome. Nat Genet 2015;47:199–208. https://doi.org/10.1038/ng.3192.Search in Google Scholar PubMed PubMed Central

50. Qiu, M, Xu, Y, Wang, J, Zhang, E, Sun, M, Zheng, Y, et al.. A novel lncRNA, LUADT1, promotes lung adenocarcinoma proliferation via the epigenetic suppression of p27. Cell Death Dis 2015;6:e1858. https://doi.org/10.1038/cddis.2015.203.Search in Google Scholar PubMed PubMed Central

51. Tong, YS, Wang, XW, Zhou, XL, Liu, ZH, Yang, TX, Shi, WH, et al.. Identification of the long non-coding RNA POU3F3 in plasma as a novel biomarker for diagnosis of esophageal squamous cell carcinoma. Mol Cancer 2015;14:3. https://doi.org/10.1186/1476-4598-14-3.Search in Google Scholar PubMed PubMed Central

52. Zhang, W, Ren, SC, Shi, XL, Liu, YW, Zhu, YS, Jing, TL, et al.. A novel urinary long non-coding RNA transcript improves diagnostic accuracy in patients undergoing prostate biopsy. Prostate 2015;75:653–61. https://doi.org/10.1002/pros.22949.Search in Google Scholar PubMed

53. Xie, Z, Chen, X, Li, J, Guo, Y, Li, H, Pan, X, et al.. Salivary HOTAIR and PVT1 as novel biomarkers for early pancreatic cancer. Oncotarget 2016;7:25408–19. https://doi.org/10.18632/oncotarget.8323.Search in Google Scholar PubMed PubMed Central

54. Wang, WW, Zhou, XL, Song, YJ, Yu, CH, Zhu, WG, Tong, YS. Combination of long noncoding RNA MALAT1 and carcinoembryonic antigen for the diagnosis of malignant pleural effusion caused by lung cancer. OncoTargets Ther 2018;11:2333–44. https://doi.org/10.2147/ott.s157551.Search in Google Scholar

55. Lv, P, Yang, S, Liu, W, Qin, H, Tang, X, Wu, F, et al.. Circulating plasma lncRNAs as novel markers of EGFR mutation status and monitors of epidermal growth factor receptor-tyrosine kinase inhibitor therapy. Thorac Cancer 2020;11:29–40. https://doi.org/10.1111/1759-7714.13216.Search in Google Scholar PubMed PubMed Central

56. Kroh, EM, Parkin, RK, Mitchell, PS, Tewari, M. Analysis of circulating microRNA biomarkers in plasma and serum using quantitative reverse transcription-PCR (qRT-PCR). Methods 2010;50:298–301. https://doi.org/10.1016/j.ymeth.2010.01.032.Search in Google Scholar PubMed PubMed Central

Received: 2022-05-27
Accepted: 2022-06-22
Published Online: 2022-07-04
Published in Print: 2022-09-27

© 2022 Walter de Gruyter GmbH, Berlin/Boston

Downloaded on 28.3.2024 from https://www.degruyter.com/document/doi/10.1515/cclm-2022-0519/html
Scroll to top button