, Volume 197, Issue 1, pp 53–60 | Cite as

Cytotoxic Natural Killer Subpopulations as a Prognostic Factor of Malignant Pleural Effusion

  • Susana Herrera LaraEmail author
  • Estrella Fernández-Fabrellas
  • Gustavo Juan Samper
  • Josefa Marco Buades
  • Rafael Andreu Lapiedra
  • Amparo Pinilla Moreno
  • María Morales Suárez-Varela



Malignant pleural effusion (MPE) is a sign of advanced disease of poor prognosis. As natural killer (NK) cells are involved in the first line of tumour defence, we aimed to validate a new diagnostic and prognostic indicator for MPE based on NK subpopulations of pleural fluid (PF) and peripheral blood (PB).


NK subpopulations were determined in PF and PB in 71 patients with malignant, paramalignant or benign pleural effusion. The receiver operating characteristic (ROC) curves, Kaplan–Meier, multivariable Cox model and decision trees created with the CHAID (Chi-square automatic interaction detector) methodology were employed.


We demonstrated that the PF/PB ratios of the CD56 bright CD16− and CD56 dim CD16− NK subpopulations were higher (p = 0.013 and p = 0.003, respectively) in MPEs and paramalignant pleural effusions (PPEs) than in benign ones, with an AUC of 0.757 and 0.741, respectively. The PF/PB ratio of CD16+ NK and CD57+ NK obtained a higher hazard ratio (HR) in the crude Cox’s regression analysis. In the adjusted Cox’s regression analysis, the PF/PB ratio of CD16+ NK gave the highest HR (HR 6.1 [1.76–21.1]) (p = 0.004). In the decision tree created for the MPE prognosis, we observed that the main predictor variable among the studied clinical, radiological, and analytical variables was lung mass, and that 92.9% of the patients who survived had a PF/PB ratio of the CD56 dim CD16+ NK subpopulation ≤ 0.43.


Our data suggest that both the PF/PB ratios of cytotoxic subpopulations CD57+ NK and CD16+ NK are useful as a prognostic factor of MPE. Other subpopulations (CD56 bright CD16− and CD56 dim CD16− NK) could help to diagnose MPE.


Biomarker Cancer Diagnosis Flow cytometry Natural killer cells Pleural effusion Prognosis 



Malignant pleural effusion


Natural killer


Pleural fluid


Peripheral blood


Receiver operating characteristic


Chi-square automatic interaction detector


Computed tomography


Paramalignant pleural effusion


Committee of Ethics and Clinical Trials


Phosphate-buffered saline


Standard deviation


ROC area under the curve


Confidence intervals


Benign pleural effusion


Hazard ratio



The authors would like to thank the Pulmonology Foundation of the Valencian Community for the grant that this work was awarded with, and with which the monoclonal antibodies employed were obtained. They also thank everyone who collaborated either directly or indirectly in this research.

Author Contributions

SHL designed and conducted the research, collected, analysed and interpreted data, and wrote the manuscript. EF-F designed and conducted the research, interpreted the data, wrote the manuscript and critically revised the article. GJS critically revised the article. JMB analysed and interpreted the data. RAL analysed and interpreted the data. APM provided technical assistance. MMS-V analysed and interpreted the data, performed the statistical analysis and critically revised the article.


Dr. Susana Herrera Lara has received research scholarship support from the Pulmonology Foundation of the Valencian Community.

Compliance with Ethical Standards

Conflict of interest

We wish to confirm that there are no known conflicts of interest associated with this publication, and there has been no financial support for this work that could have influenced its outcome.

Ethical Approval

We further confirm that any aspect of the work covered herein that has involved human patients has been conducted with the ethical approval of all the relevant bodies, and that such approvals are acknowledged in the manuscript.


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Susana Herrera Lara
    • 1
    Email author
  • Estrella Fernández-Fabrellas
    • 2
  • Gustavo Juan Samper
    • 2
  • Josefa Marco Buades
    • 3
  • Rafael Andreu Lapiedra
    • 4
  • Amparo Pinilla Moreno
    • 3
  • María Morales Suárez-Varela
    • 5
    • 6
  1. 1.Pulmonology DepartmentDr Peset University HospitalValenciaSpain
  2. 2.Pulmonology DepartmentGeneral University Consorci HospitalValenciaSpain
  3. 3.Hematology DepartmentDr Peset University HospitalValenciaSpain
  4. 4.Hematology DepartmentLa Fe University and Polytechnic HospitalValenciaSpain
  5. 5.Unit of Public Health and Environmental Care, Department of Preventive MedicineUniversity of ValenciaValenciaSpain
  6. 6.Biomedical Research Centre Network on Epidemiology and Public Health (CIBERESP)Institute of Health Carlos IIIMadridSpain

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