Biomarkers in the diagnosis of pleural diseases: a 2018 update

Our plain-English summary of Biomarkers in the diagnosis of pleural diseases: a 2018 update, by J.M. Porcel (Therapeutic Advances in Respiratory Disease, 2018).

The study

• Author: J.M. Porcel
• Journal: Therapeutic Advances in Respiratory Disease
• Published: 2018;12:1753466618808660
• Type of article: Review
• Cited by: 92 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The use of biomarkers on pleural fluid (PF) specimens may assist the decision-making process and enhance clinical diagnostic pathways. Three paradigmatic examples are heart failure, tuberculosis and, particularly, malignancy. An elevated PF concentration of the amino-terminal fragment of probrain natriuretic peptide (>1500 pg/ml) is a hallmark of acute decompensated heart failure. Adenosine deaminase, interferon-γ and interleukin-27 are three valuable biomarkers for diagnosing tuberculous pleurisy, yet only the first has been firmly established in clinical practice. Diagnostic PF biomarkers for malignancy can be classified as soluble-protein based, immunocytochemical and nucleic-acid based. Soluble markers (e.g. carcinoembryonic antigen (CEA), carbohydrate antigen 15-3, mesothelin) are only indicative of cancer, but not confirmatory. Immunocytochemical studies on PF cell blocks allow: (a) to distinguish mesothelioma from reactive mesothelial proliferations (e.g. loss of BAP1 nuclear expression, complemented by the demonstration of p16 deletion using fluorescence in situ hybridization, indicate mesothelioma); (b) to separate mesothelioma from adenocarcinoma (e.g. calretinin, CK 5/6, WT-1 and D2-40 are markers of mesothelioma, whereas CEA, EPCAM, TTF-1, napsin A, and claudin 4 are markers of carcinoma); and (c) to reveal tumor origin in pleural metastases of an unknown primary site (e.g. TTF-1 and napsin A for lung adenocarcinoma, p40 for squamous lung cancer, GATA3 and mammaglobin for breast cancer, or synaptophysin and chromogranin A for neuroendocrine tumors). Finally, PF may provide an adequate sample for analysis of molecular markers to guide patients with non-small cell lung cancer to appropriate targeted therapies. Molecular testing must include, at least, mutations of epidermal growth-factor receptor and BRAF V600E, translocations of rat osteosarcoma and anaplastic lymphoma kinase, and expression of programmed death ligand 1.

In plain English

This article was a single-author narrative review of biomarkers measured in pleural fluid to help find the cause of a pleural effusion, covering heart failure, tuberculosis and, especially, cancer, including mesothelioma. It studied no patients and no asbestos exposure of its own. Its figures came from earlier studies and meta-analyses. For mesothelioma, the review reported that pleural fluid cytology has a sensitivity usually quoted at around 30%, and that no soluble biomarker has acceptable accuracy. In one cited meta-analysis, pleural fluid mesothelin had 79% sensitivity and 85% specificity. The review reported BAP1 protein loss in 55% to 80% of epithelioid mesotheliomas and p16 deletions in up to 80% of pleural mesotheliomas, with neither found in reactive mesothelial cells. The author concluded that there is enough evidence for testing BAP1 loss and p16 deletion when telling mesothelioma apart from benign reactive mesothelial cells, though these markers are not yet widely employed.

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: Narrative review by a single author; no original data collected
• Who was studied: No study population of its own. The review covered published studies, meta-analyses and guidelines on pleural fluid biomarkers for heart failure, tuberculosis and malignancy (including mesothelioma), with emphasis on malignancy.
• Exposure: Not an exposure study. Asbestos exposure was not examined. Asbestos appears only once, as the control group (asbestos-exposed controls) of a cited micro-RNA study.
• Main results:
  • For mesothelioma, the review reported that pleural fluid cytology has low sensitivity, usually quoted at around 30%.
  • The review stated there are no soluble biomarkers with acceptable accuracy to identify mesothelioma.
  • In one cited meta-analysis, soluble mesothelin had a sensitivity of 79% in pleural fluid and 61% in serum, with pooled specificities of 85% and 87% respectively.
  • The reported frequency of BAP1 protein loss in epithelioid mesotheliomas ranged from 55% to 80% (from cited sources).
  • p16 deletions were reported in up to 80% of pleural mesotheliomas: 90 to 100% of the sarcomatoid subtype and 70% of the epithelioid and biphasic subtypes (from cited sources).
  • The review stated that neither BAP1 loss nor p16 deletions occur in reactive mesothelial cells (from a cited source).
  • A cited study of pleural fluid cell blocks from 258 patients with malignant effusions, 53 of whom had mesothelioma, found BAP1 loss in 87% of mesotheliomas compared with 2% of various metastatic carcinomas.
  • A cited study found plasma levels of two micro-RNAs lower in 22 patients with mesothelioma than in 44 asbestos-exposed controls. The two combined gave 77% sensitivity and 86% specificity for mesothelioma.
• The authors' conclusion: The author concluded that there is enough evidence for testing BAP1 loss by immunocytochemistry and p16 deletion by FISH when differentiating mesothelioma from reactive benign mesothelial cells, though these markers are not yet widely employed.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Pleural plaques and thickening.

Medical terms in this study, explained in our Lexicon: Biomarker, Tuberculous pleurisy, Carcinoembryonic Antigen (CEA), Mesothelin, Cell Block, Mesothelioma, BAP1, Fluorescence In Situ Hybridization (FISH).

Related studies

• Utility of hyaluronic acid in pleural fluid for differential diagnosis of pleural effusions: likelihood ratios for malignant mesothelioma — S. Atagi, M. Ogawara, et al. (1997)
• Vascular endothelial growth factor in pleural fluid for differential diagnosis of benign and malignant origin and its clinical applications — A. Fiorelli, G. Vicidomini, et al. (2011)
• Calretinin. A selective marker of normal and neoplastic mesothelial cells in serous effusions — M.C. Barberis, M. Faleri, et al. (1997)
• Significance of secretory leukocyte peptidase inhibitor in pleural fluid for the diagnosis of benign asbestos pleural effusion — T. Kishimoto, Y. Kojima, et al. (2021)
• Predicting Malignant and Paramalignant Pleural Effusions by Combining Clinical, Radiological and Pleural Fluid Analytical Parameters — S. Herrera Lara, E. Fernández-Fabrellas, et al. (2017)
• Natriuretic peptides in pleural effusions: Beyond a diagnosis of heart failure — J.M. Porcel (2020)

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