Identifying Thoracic Malignancies Through Pleural Fluid Biomarkers: A Predictive Multivariate Model

Our plain-English summary of Identifying Thoracic Malignancies Through Pleural Fluid Biomarkers: A Predictive Multivariate Model, by J.M. Porcel, A. Esquerda, M. Martínez-Alonso, et al (Medicine, 2016).

The study

• Authors: J.M. Porcel, A. Esquerda, M. Martínez-Alonso, S. Bielsa, A. Salud
• Journal: Medicine
• Published: 2016;95(10):e3044
• Type of article: Randomized trial
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The diagnosis of malignant pleural effusions may be challenging when cytological examination of aspirated pleural fluid is equivocal or noncontributory. The purpose of this study was to identify protein candidate biomarkers differentially expressed in the pleural fluid of patients with mesothelioma, lung adenocarcinoma, lymphoma, and tuberculosis (TB).A multiplex protein biochip comprising 120 biomarkers was used to determine the pleural fluid protein profile of 29 mesotheliomas, 29 lung adenocarcinomas, 12 lymphomas, and 35 tuberculosis. The relative abundance of these predetermined biomarkers among groups served to establish the differential diagnosis of: malignant versus benign (TB) effusions, lung adenocarcinoma versus mesothelioma, and lymphoma versus TB. The selected putative markers were validated using widely available commercial techniques in an independent sample of 102 patients.Significant differences were found in the protein expressions of metalloproteinase-9 (MMP-9), cathepsin-B, C-reactive protein, and chondroitin sulfate between malignant and TB effusions. When integrated into a scoring model, these proteins yielded 85% sensitivity, 100% specificity, and an area under the curve (AUC) of 0.98 for labeling malignancy in the verification sample. For lung adenocarcinoma-mesothelioma discrimination, combining CA19-9, CA15-3, and kallikrein-12 had maximal discriminatory capacity (65% sensitivity, 100% specificity, AUC 0.94); figures which also refer to the validation set. Last, cathepsin-B in isolation was only moderately useful (sensitivity 89%, specificity 62%, AUC 0.75) in separating lymphomatous and TB effusions. However, this last differentiation improved significantly when cathepsin-B was used with respect to the patient's age (sensitivity 72%, specificity 100%, AUC 0.94).In conclusion, panels of 4 (i.e., MMP-9, cathepsin-B, C-reactive protein, chondroitin sulfate), or 3 (i.e., CA19-9, CA15-3, kallikrein-12) different protein biomarkers on pleural fluid samples are highly discriminative for signaling a malignant versus tuberculous effusion, or lung adenocarcinoma versus mesothelioma, respectively. Cathepsin-B could also be helpful in establishing the presence of a lymphomatous effusion versus that of TB, if the patient's age is simultaneously taken into consideration.

In plain English

This diagnostic accuracy study, from a hospital in Lleida, Spain, tested whether proteins in pleural fluid (fluid collected from around the lungs) could tell different causes of pleural effusion apart. The article does not report on asbestos exposure. Using a chip that measured 120 proteins, the authors compared stored fluid from 29 patients with mesothelioma (from a hospital in Sevilla), 29 with lung adenocarcinoma, 12 with lymphoma and 35 with tuberculosis. They then rechecked selected proteins with standard laboratory tests in a separate group of 102 patients. In that check group, a score built from four proteins (MMP-9, chondroitin sulfate, cathepsin-B and C-reactive protein) flagged 85% of 20 cancers and none of 20 tuberculosis cases. A score from CA19-9, CA15-3 and kallikrein-12 flagged 65% of 20 lung adenocarcinomas and none of 20 mesotheliomas. Cathepsin-B alone separated lymphoma from tuberculosis less well, and did better when combined with patient age. The authors stated that their numbers were small and that larger validation is needed. They said the panels are not meant to replace pleural fluid cytology or biopsy.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Diagnostic accuracy study using stored pleural fluid samples: a derivation set tested on a 120-protein antibody microarray chip, and selected proteins then validated with commercial assays in an independent sample
• Who was studied: Derivation sample of 105 patients after 3 exclusions: 29 mesotheliomas, 29 lung adenocarcinomas, 12 lymphomas with high pleural fluid ADA, and 35 tuberculosis. Lung adenocarcinoma, lymphoma and tuberculosis samples were collected 2001 to 2011 at Arnau de Vilanova University Hospital, Lleida, Spain. Mesothelioma samples came from Hospital Universitario Virgen del Rocío, Sevilla, Spain. Validation sample of 102 patients: 30 lung adenocarcinomas, 20 mesotheliomas, 34 tuberculosis, and 18 lymphomas.
• Main results:
  • Validation set, malignant (10 lung adenocarcinomas, 5 mesotheliomas, 5 lymphomas) versus 20 tuberculosis effusions: a score combining MMP-9, chondroitin sulfate, cathepsin-B and C-reactive protein had an AUC of 0.98 (95% CI 0.95–1). A score of 6 or more (6–9 per Table 3) indicated malignancy with 85% sensitivity (95% CI 62.1–96.8%) and 100% specificity (95% CI 83.2–100%).
  • Validation set, 20 lung adenocarcinomas versus 20 mesotheliomas: a score combining CA19-9, kallikrein-12 and CA15-3 had an AUC of 0.94 (95% CI 0.88–1). A score of 4 or more (4–6 per Table 3) separated lung adenocarcinomas from mesotheliomas with 65% sensitivity (95% CI 40.8–84.6%) and 100% specificity (95% CI 83.2–100%).
  • Validation set, 18 lymphomas versus 34 tuberculosis: a pleural fluid cathepsin-B level below 0.31 ng/mL gave 89% sensitivity (95% CI 65.3–98.6%), 62% specificity (95% CI 43.6–77.8%), and AUC 0.75 (95% CI 0.64–0.86).
  • For lymphoma versus tuberculosis, combining cathepsin-B below 0.31 ng/mL with an age cutoff of 50 years gave sensitivity 72.2% (95% CI 46.5–90.3%), specificity 100% (95% CI 89.7–100%), and AUC 0.94 (95% CI 0.88–0.99). Adding age or sex did not improve the other two scoring models.
  • Derivation set: a classification tree with MMP-9, cathepsin-B, C-reactive protein, angiostatin and chondroitin sulfate separated 58 malignant effusions (29 lung adenocarcinomas, 29 mesotheliomas) from paired tuberculosis effusions with 95% sensitivity (95% CI 86–99%) and 84.7% specificity (95% CI 73–92.8%).
  • On the chip, soluble mesothelin was not found to be differentially expressed in mesotheliomas compared with lung adenocarcinomas.
• The authors' conclusion: The authors concluded that the protein panels showed diagnostic power for separating malignant from tuberculous effusions and lung adenocarcinoma from mesothelioma. They concluded that cathepsin-B combined with age may help separate lymphoma from tuberculosis. They stated the panels are not intended to replace pleural fluid cytology or biopsy, but may add information when deciding on invasive procedures.
• Limitations the authors state:
  • A relatively small number of pleural fluid samples was tested, particularly lymphomas. No biomarker set for separating lymphoma from tuberculosis could be firmly verified without adding age.
  • Benign effusions other than tuberculosis were not studied, so the accuracy may not apply to separating malignant from non-tuberculosis effusions.
  • The biomarkers need validation in new, large independent populations and in cancer patients with falsely negative or misleading pleural fluid cytology.

Topics

Medical terms in this study, explained in our Lexicon: Biomarker, Pleural Effusion, Mesothelioma, Lung Adenocarcinoma, Differential Diagnosis.

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