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. 2023 Nov 22;15(23):5534.
doi: 10.3390/cancers15235534.

Validation of a Gene Expression Approach for the Cytological Diagnosis of Epithelioid and Biphasic Pleural Mesothelioma on a Consecutive Series

Rossella Bruno  1 , Anello Marcello Poma  2 , Greta Alì  2 , Agnese Proietti  1 , Alessandro Ribechini  3 , Antonio Chella  4 , Gabriella Fontanini  2
Affiliations

Validation of a Gene Expression Approach for the Cytological Diagnosis of Epithelioid and Biphasic Pleural Mesothelioma on a Consecutive Series

Rossella Bruno et al. Cancers (Basel). .

Abstract

Cytological diagnosis of pleural mesothelioma (PM) is controversial, even using ancillary markers (BAP1, MTAP and CDKN2A). Here, we aimed to prospectively validate a previously developed 117-gene expression panel for the differential cytological diagnosis of epithelioid, biphasic PM and mesothelial hyperplasia. Seventy-seven pleural effusions were classified using the 117-gene expression levels (NanoString system). Sixty-eight cases were also screened for ancillary markers. The performance of both gene panel and ancillary markers was evaluated using ROC metrics. A score using the top consistently deregulated genes between epithelioid and biphasic PM was built to subtype malignant effusions. The panel alone reached a diagnostic accuracy (0.89) comparable to the best marker combination (BAP1 plus MTAP: 0.88). Ancillary tests missed 8 PMs, 7 of which were correctly classified by the panel. The score built by averaging the expression levels of MSLN, CLDN15 and CFB showed an accuracy of 0.80 in subtyping epithelioid and biphasic effusions. The 117-gene panel is effective for PM cytological diagnosis of epithelioid and biphasic PM. This tool can be complementary to ancillary markers, reducing invasive procedures and allowing an earlier diagnosis. Finally, the possibility to subtype PM on effusions strengthens the panel's role in PM diagnosis and management.

Keywords: gene expression; mesothelial hyperplasia; pleural effusions; pleural mesothelioma; subtyping.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Ancillary tests for mesothelioma differential diagnosis. (A) Epithelioid pleural mesothelioma retaining BAP1 expression (magnification 10×). (B) Epithelioid pleural mesothelioma retaining MTAP expression (magnification 10×). (C) Epithelioid pleural mesothelioma without p16 deletion (magnification 10×). (D) Epithelioid pleural mesothelioma with BAP1 loss of expression (magnification 10×). (E) Epithelioid pleural mesothelioma with MTAP loss of expression (magnification 60×). (F) Epithelioid pleural mesothelioma with p16 deletion (magnification 60×).
Figure 2
Figure 2
Principal component analysis and unsupervised clustering. (A) Principal component analysis was performed on normalized log2 counts. A degree of separation between MH and PM can be observed on principal component 1. (B) Unsupervised clustering of samples using scaled and centered counts was performed based on Euclidean distance and using Ward’s method. Two main clusters were produced: one specific for malignant cases and the other enriched with benign pleural effusions. Red and blue indicate a high and low gene expression level, respectively. Each column represents a single sample, and each row represents a single gene. MH, reactive mesothelial hyperplasia; PM, pleural mesothelioma; ePM, epithelioid pleural mesothelioma; bPM, biphasic pleural mesothelioma.
Figure 3
Figure 3
ROC curves: ROC curves of ancillary tests alone or in combination with the 117-gene panel. AUC, area under the curve.
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