Improved diagnosis and prognostication of patients with pleural malignant mesothelioma using biomarkers in pleural effusions and peripheral blood samples - a short report

Our plain-English summary of Improved diagnosis and prognostication of patients with pleural malignant mesothelioma using biomarkers in pleural effusions and peripheral blood samples - a short report, by N. Beije, J. Kraan, M.A. den Bakker, et al (Cellular Oncology, 2017).

The study

• Authors: N. Beije, J. Kraan, M.A. den Bakker, A.P.W.M. Maat, C. van der Leest, R. Cornelissen, N.M. Van, J.W.M. Martens, J.G.J.V. Aerts, S. Sleijfer
• Journal: Cellular Oncology
• Published: 2017;40(5):511-519
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Purpose: There is a lack of robust and clinically utilizable markers for the diagnosis and prognostication of malignant pleural mesothelioma (MPM). This research was aimed at optimizing and exploring novel approaches to improve the diagnosis and prognostication of MPM in pleural effusions and peripheral blood samples.

Methods: CellSearch-based and flow cytometry-based assays using melanoma cell adhesion molecule (MCAM) to identify circulating tumor cells (CTCs) in pleural effusions and peripheral blood samples of MPM patients were optimized, validated, explored clinically and, in case of pleural effusions, compared with cytological analyses. Additionally, tumor-associated circulating endothelial cells (CECs) were measured in peripheral blood samples. The assays were performed on a MPM cohort encompassing patients with histology-confirmed MPM (n=27) and in a control cohort of patients with alternative diagnoses (n=22). Exploratory analyses on the prognostic value of all assays were also performed.

Results: The malignancy of MCAM-positive cells in pleural effusions from MPM patients was confirmed. The detection of MPM CTCs in pleural effusions by CellSearch showed a poor specificity. The detection of MPM CTCs in pleural effusions by flow cytometry showed a superior sensitivity (48%) to standard cytological analysis (15%) (p = 0.03). In peripheral blood, CTCs were detected in 26% of the MPN patients, whereas in 42% of the MPM patients tumor-associated CECs were detected above the upper limit of normal (ULN). In exploratory analyses the absence of CTCs in pleural effusions, and tumor-associated CECs in peripheral blood samples above the ULN, appeared to be associated with a worse overall survival.

Conclusion: MCAM-based flow cytometric analysis of pleural effusions is more sensitive than routine cytological analysis. Flow cytometric analysis of pleural effusions and tumor-associated CECs in peripheral blood may serve as a promising approach for the prognostication of MPM patients and, therefore, warrants further study.

In plain English

This prospective study at two Dutch centers (March 2014 to January 2016) tested MCAM-based laboratory methods for finding malignant pleural mesothelioma (MPM) cells in pleural fluid and blood. It included 27 patients with MPM and 22 control patients whose pleural fluid had other causes. A table recorded asbestos exposure (labeled "asbestosis exposure") for 20 of the 27 MPM patients. With one method, CellSearch, cells meeting the tumor-cell criteria were found in 21 of 23 tested MPM patients (91%) and 17 of 18 tested controls (94%), so this part was stopped early. A second method, flow cytometry, found cells meeting its mesothelioma-cell criteria in 12 of 25 MPM patients (48%) and in one control, counted by the authors as a false positive. Among 20 MPM patients with matched results, a pathologist's fluid examination identified 3 (15%); flow cytometry identified 6 more (p = 0.03). Tumor cells were found in the blood of 6 of 23 MPM patients. In exploratory survival analyses with few patients, not finding tumor cells in the fluid, and high tumor-associated circulating endothelial cells, appeared associated with worse survival. The authors called for larger studies.

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: Prospective two-cohort diagnostic study, preceded by laboratory tests on MPM cell lines and DNA (SNP array) analysis of sorted pleural fluid cells; survival analyses were exploratory
• Who was studied: 49 patients at two centers in The Netherlands (Erasmus MC Cancer Institute, Rotterdam, and Amphia Hospital, Breda), March 2014 to January 2016: 27 with malignant pleural mesothelioma (81% epithelial type) and 22 controls with pleural effusions from other causes (52% malignant, 48% benign)
• Exposure: The study did not examine asbestos exposure as a risk factor. It tested MCAM-based detection of tumor cells in pleural fluid and blood, and of tumor-associated circulating endothelial cells in blood. The baseline table, under the label "Asbestosis exposure", lists yes for 20 MPM patients and 6 controls, no for 7 MPM patients and 3 controls, and unknown for 0 MPM patients and 13 controls.
• Main results:
  • Pleural fluid from 41 patients could be evaluated with CellSearch MCAM-based enrichment. Cells meeting the tumor-cell criteria were found in 21 of 23 MPM patients (91%) and 17 of 18 control patients (94%). Median cell counts were 416 per 3 ml (MPM) and 440 per 3 ml (controls), p = 0.86.
  • Because of this limited specificity, the CellSearch part of the study was discontinued early.
  • Flow cytometry detected cells meeting the study's criteria for MPM tumor cells in the pleural fluid of 12 of 25 MPM patients (48%). Such cells were also detected in one control patient (6%), which the authors counted as one false-positive finding, giving a specificity of 94%. No such cells were detected in 4 patients with biphasic MPM.
  • In paired comparisons (20 MPM patients, 18 controls), the pathologist's review of fluid cytology correctly identified 3 MPM patients (sensitivity 15%, specificity 100%). Flow cytometry identified 6 additional MPM patients (McNemar p = 0.03).
  • In two MPM patients, MCAM-positive cells sorted from pleural fluid showed DNA copy number changes that were absent in the same patients' white blood cells. The authors took this as supporting the malignant nature of these cells.
  • Circulating tumor cells were found in the blood of 6 of 23 MPM patients (26%).
  • Of 24 MPM patients with blood results, 10 (42%) had tumor-associated circulating endothelial cells above the upper limit of normal (8 or more per 4 ml).
  • In exploratory analyses, the absence of tumor cells in pleural fluid and tumor-associated circulating endothelial cells above the upper limit of normal appeared to be associated with worse overall survival. Blood tumor cells and endothelial cell counts above the median did not appear to be associated with survival.
• The authors' conclusion: The authors concluded that MCAM-positive cells in the pleural fluid of MPM patients are malignant, and that several of these biomarkers may improve the diagnosis and prognosis of MPM. They stated that larger MPM cohorts should be studied.
• Limitations the authors state:
  • The survival analyses were exploratory only, because there were few patients and events, and no formal statistics could be performed on the survival curves.
  • The authors said the single false-positive flow cytometry result should be interpreted with caution, because that control patient was clinically suspected of MPM, although MPM was not confirmed during 1.5 years of follow-up.
  • No cytology slides were available to compare flow cytometry with MCAM staining on slides.
  • The survival finding for pleural fluid tumor cells is preliminary and needs validation in a larger cohort.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Biomarker, Pleural Effusion, Pleural Mesothelioma, Histology, Overall Survival.

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