Use of a panel of tumor markers (carcinoembryonic antigen, cancer antigen 125, carbohydrate antigen 15-3, and cytokeratin 19 fragments) in pleural fluid for the differential diagnosis of benign and malignant effusions

Chest. 2004 Dec;126(6):1757-63. doi: 10.1378/chest.126.6.1757.


Study objective: The diagnostic value of tumor markers in pleural fluid is subject to debate. The aim of this study was to evaluate the diagnostic performance of several tumor markers in common use for detecting malignant pleural disease.

Design: Blinded comparison of four tumor markers in pleural fluid with a confirmatory diagnosis of malignancy by pleural cytology or thoracoscopic biopsy.

Setting: Two teaching hospitals in Spain.

Patients and methods: A total of 416 patients (166 with definite malignant effusions, 77 with probable malignant effusions, and 173 with benign effusions) were enrolled. Among them, there were 42 patients recruited from one of the participant centers with thoracoscopic facilities, who had false-negative fluid cytology findings and malignancy confirmed by medical thoracoscopy. Tumor markers in pleural fluid were determined either by electrochemiluminescence immunoassay (carcinoembryonic antigen [CEA], carbohydrate antigen 15-3 [CA 15-3], cytokeratin 19 fragments [CYFRA 21-1]) or microparticle enzyme immunoassay (cancer antigen 125 [CA 125]) technologies. Cutoff points that yielded 100% specificity (ie, all patients with benign effusions had levels below this cutoff) were selected for each marker.

Results: Malignant pleural effusions (PEs) had higher levels of pleural fluid markers than did effusions due to benign conditions. At 100% specificity, a pleural CEA > 50 ng/mL, CA 125 > 2,800 U/mL, CA 15-3 > 75 U/mL, and CYFRA 21-1 > 175 ng/mL had 29%, 17%, 30%, and 22% overall sensitivities, respectively. The combination of the four tumor markers reached 54% sensitivity, whereas the combined use of the cytology and the tumor marker panel increased the diagnostic yield of the former by 18% (95% confidence interval, 13 to 23%). More than one third of cytology-negative malignant PEs could be identified by at least one marker of the panel.

Conclusions: No single pleural fluid marker seems to be accurate enough as to be introduced in the routine workup of PE diagnosis. However, a tumor marker panel may represent a helpful adjunct to cytology in order to rule in malignancy as a probable diagnosis, thus guiding the selection of patients who might benefit from further invasive procedures.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antigens, Neoplasm / analysis
  • Biomarkers, Tumor / analysis*
  • CA-125 Antigen / analysis
  • Carcinoembryonic Antigen / analysis
  • Cytodiagnosis
  • Diagnosis, Differential
  • Female
  • Humans
  • Keratin-19
  • Keratins
  • Male
  • Mucin-1 / analysis
  • Pleural Effusion / chemistry
  • Pleural Effusion / diagnosis
  • Pleural Effusion, Malignant / chemistry
  • Pleural Effusion, Malignant / diagnosis*
  • Pleural Effusion, Malignant / etiology
  • ROC Curve
  • Sensitivity and Specificity


  • Antigens, Neoplasm
  • Biomarkers, Tumor
  • CA-125 Antigen
  • Carcinoembryonic Antigen
  • Keratin-19
  • Mucin-1
  • antigen CYFRA21.1
  • Keratins