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Malignant pleural mesothelioma (MPM) is a rare asbestos related cancer, aggressive and unresponsive to therapies. Histological examination of pleural lesions is the gold standard of MPM diagnosis, although it is sometimes hard to discriminate the epithelioid type of MPM from benign mesothelial hyperplasia (MH).This work aims to define a new molecular tool for the differential diagnosis of MPM, using the expression profile of 117 genes deregulated in this tumour.The gene expression analysis was performed by nanoString System on tumour tissues from 36 epithelioid MPM and 17 MH patients, and on 14 mesothelial pleural samples analysed in a blind way. Data analysis included raw nanoString data normalization, unsupervised cluster analysis by Pearson correlation, non-parametric Mann Whitney U-test and molecular classification by the Uncorrelated Shrunken Centroid (USC) Algorithm.The Mann-Whitney U-test found 35 genes upregulated and 31 downregulated in MPM. The unsupervised cluster analysis revealed two clusters, one composed only of MPM and one only of MH samples, thus revealing class-specific gene profiles. The Uncorrelated Shrunken Centroid algorithm identified two classifiers, one including 22 genes and the other 40 genes, able to properly classify all the samples as benign or malignant using gene expression data; both classifiers were also able to correctly determine, in a blind analysis, the diagnostic categories of all the 14 unknown samples.In conclusion we delineated a diagnostic tool combining molecular data (gene expression) and computational analysis (USC algorithm), which can be applied in the clinical practice for the differential diagnosis of MPM.

Introduction: Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm associated with asbestos exposure. Currently, the molecular mechanisms that induce MPM development are still unknown. The purpose of this study was to identify new molecular biomarkers for mesothelial carcinogenesis., Methods: We analyzed a panel of 84 genes involved in extracellular matrix remodeling and cell adhesion by polymerase chain reaction (PCR) array in 15 samples of epithelioid mesothelioma and 10 samples of reactive mesothelial hyperplasia (MH; 3 of 25 samples were inadequate for mRNA analysis). To validate the differentially expressed genes identified by PCR array, we analyzed 27 more samples by immunohistochemistry, in addition to the 25 samples already studied., Results: Twenty-five genes were differentially expressed in MPM and MH by PCR array. Of these we studied matrix metalloproteinase 7 (MMP7), MMP14, CD44, and integrin, alpha3 expression by immunohistochemistry in 26 epithelioid MPM and 26 MH samples from the entire series of 52 cases. We observed higher MMP14 and integrin, alpha3 expression in MPM samples compared with MH samples (p = 0.000002 and p = 0.000002, respectively). Conversely, CD44 expression was low in most (57.7%) mesothelioma samples but only in 11.5% of the MH samples (p = 0.0013). As regards MMP7, we did not observe differential expression between MH and MPM samples., Conclusions: We have extensively studied genes involved in cell adhesion and extracellular matrix remodeling in MPM and MH samples, gaining new insight into the pathophysiology of mesothelioma. Moreover, our data suggest that these factors could be potential biomarkers for MPM.

Introduction: Malignant pleural mesothelioma is a highly aggressive neoplasm with an incidence that is increasing world-wide. Mast cells are part of the innate immune system and have been associated with different solid tumors, but there is controversy surrounding their pro- and antitumorigenic effects in cancers. There are two subsets of human mast cells, resulting from the expression of different enzymes: tryptase positive mast cells and chymase positive mast cells. The purpose of this study was to determine the presence and prognostic significance of tumor infiltrating mast cells in mesothelioma., Methods: Tryptase and chymase mast cell counts were determined by immunohistochemistry in 60 patients with mesothelioma. All pathologic samples were from patients who underwent treatment with intrapleural preoperative interleukin-2 (18 x 10(6) IU/d for 3 days). After one day of recovery, patients underwent surgery. Pleural samples were also immunostained for CD34 to evaluate microvessel count., Results: High tryptase mast cells counts were found in the majority (73.3%) of the cases studied, and the results were significantly associated with both overall survival (p = 0.02) and time to progression (p = 0.01). This finding was confirmed using multivariate analysis: a higher tryptase mast cells count emerged as an independent favorable prognostic factor (p = 0.02). However, tryptase mast cells count did not show significant correlation with microvessel count., Conclusions: These results suggest that tumor infiltrating tryptase mast cells, after interleukin-2 preoperative induction therapy, predict improved clinical outcome in patients with malignant pleural mesothelioma, and highlight the critical role of the local inflammatory response in mesothelioma cancer progression.

Simple Summary: The Hippo pathway is the most commonly altered signaling in pleural mesothelioma (PM). The aim of our retrospective study was to stratify patients with epithelioid PM using the expression levels of the Hippo-TEAD network. We identified two groups of tumors; HP2 tumors, which are about one-third of the total, have higher levels of downstream Hippo oncogenes, lower mRNA levels of the immune checkpoint VISTA, and poorer progression-free and overall survival. These tumors often harbor homodeletion of Hippo core suppressors. Background. The Hippo pathway is the most frequently altered signaling in pleural mesothelioma (PM). Epithelioid PM (ePM) is associated with better outcome than non-epithelioid subtypes, but its prognosis can be heterogeneous. Here, we tried to stratify ePM using the expression levels of the Hippo-TEAD network. Methods. Thirty patients with ePM were included in this study. Tumors were stratified using the expression levels of 74 genes belonging to the Hippo-TEAD network and using the non-negative matrix factorization algorithm. Results were validated using ePM cases from the TCGA cohort. Alterations associated with the molecular subgroups were investigated using mutation and copy number alteration data from TCGA. Results. Two groups of ePM (i.e., HP1 and HP2) were identified and validated using TCGA data. HP2 comprises about one-third of tumors. These tumors are frequently high-grade (73% vs. 35%), have higher levels of downstream Hippo effectors (i.e., YAP1, WWTR1 and TEADs), lower levels of VSIR—which encodes for VISTA—and poorer PFS and OS. HP2 tumors commonly harbor homodeletions in Hippo core suppressors (25% vs. 3%), while no specific gene mutation or copy number alterations of Hippo genes was associated with the two groups. Conclusions. ePM can be stratified in prognostic subtypes based on the expression levels of the Hippo-TEAD network. Higher levels of downstream Hippo effectors are associated with poor response to platinum-pemetrexed doublet and worse OS. The stratification of ePM based on the activation of the YAP/TAZ-TEAD axis is an intriguing approach in the light of the inhibitors of this signaling that are currently under investigation. [ABSTRACT FROM AUTHOR]

Simple Summary: Pleural effusions are common clinical manifestations of pleural mesothelioma (PM) and often constitute the only available biological material for diagnosis. However, the cytological diagnosis of PM can be challenging. Over the years, ancillary tests, mainly based on the analysis of single biomarkers, have been developed to differentiate malignant from benign effusions, but their sensitivity is limited. In this study, we validated, on a consecutive series, a previously defined 117-gene expression panel as a diagnostic tool for the cytological diagnosis of PM. This gene panel proved to be useful not only in the differential diagnosis of PM and mesothelial hyperplasia but also in the discrimination of the two most common PM subtypes (epithelioid and biphasic) on cytology. Once the malignancy is assessed, the PM subtype definition strongly impacts therapy and prognosis. In this context, the 117-gene panel could be a powerful diagnostic tool to improve the clinical management of PM patients. 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. [ABSTRACT FROM AUTHOR]

Pleural mesothelioma (PM) comprises three main subtypes: epithelioid, biphasic and sarcomatoid, which have different impacts on prognosis and treatment definition. However, PM subtyping can be complex given the inter- and intra-tumour morphological heterogeneity. We aim to use immunohistochemistry (IHC) to evaluate five markers (Mesothelin, Claudin-15, Complement Factor B, Plasminogen Activator Inhibitor 1 and p21-activated Kinase 4), whose encoding genes have been previously reported as deregulated among PM subtypes. Immunohistochemical expressions were determined in a case series of 73 PMs, and cut-offs for the epithelioid and non-epithelioid subtypes were selected. Further validation was performed on an independent cohort (30 PMs). For biphasic PM, the percentage of the epithelioid component was assessed, and IHC evaluation was also performed on the individual components separately. Mesothelin and Claudin-15 showed good sensitivity (79% and 84%) and specificity (84% and 73%) for the epithelioid subtype. CFB and PAK4 had inferior performance, with higher sensitivity (89% and 84%) but lower specificity (64% and 36%). In the biphasic group, all markers showed different expression when comparing epithelioid with sarcomatoid areas. Mesothelin, Claudin-15 and CFB can be useful in subtype discrimination. PAI1 and PAK4 can improve component distinction in biphasic PM. [ABSTRACT FROM AUTHOR]

The 2021 WHO Classification of Tumors of the Pleura has introduced significant changes in mesothelioma codification beyond the three current histological subtypes—epithelioid, sarcomatoid and biphasic. Major advances since the 2015 WHO classification include nuclear grading and the introduction of architectural patterns, cytological and stromal features for epithelioid diffuse mesothelioma. Mesothelioma in situ has been recognized as a diagnostic category. Demonstration of loss of BAP1 or MTAP by immunohistochemistry, or CDKN2A homozygous deletion by FISH, is valuable in establishing the diagnosis of epithelioid mesothelioma. Recent emerging data proved that grading and histological subtypes have prognostic implications and may be helpful to patient risk stratification and clinical management. Nevertheless, the latest mesothelioma classification increases the already non-negligible diagnostic pitfalls, especially concerning differential diagnosis of pre-invasive tumors. In this review, recent changes in histologic classification of mesothelioma and advances in molecular markers are presented and their relation to diagnostic challenges and prognostic implications is discussed. [ABSTRACT FROM AUTHOR]

Germline mutations in the tumor suppressor gene BRCA1-associated protein-1 (BAP1) lead to BAP1 tumor predisposition syndrome (BAP1-TPDS), characterized by high susceptibility to several tumor types, chiefly melanoma, mesothelioma, renal cell carcinoma, and basal cell carcinoma. Here, we present the results of our ten-year experience in the molecular diagnosis of BAP1-TPDS, along with a clinical update and cascade genetic testing of previously reported BAP1-TPDS patients and their relatives. Specifically, we sequenced germline DNA samples from 101 individuals with suspected BAP1-TPDS and validated pathogenic variants (PVs) by assessing BAP1 somatic loss in matching tumor specimens. Overall, we identified seven patients (7/101, 6.9%) carrying six different germline BAP1 PVs, including one novel variant. Consistently, cascade testing revealed a total of seven BAP1 PV carriers. In addition, we explored the mutational burden of BAP1-TPDS tumors by targeted next-generation sequencing. Lastly, we found that certain tumors present in PV carriers retain a wild-type BAP1 allele, suggesting a sporadic origin of these tumors or a functional role of heterozygous BAP1 in neoplastic development. Altogether, our findings have important clinical implications for therapeutic response of BAP1-TPDS patients. [ABSTRACT FROM AUTHOR]

Biphasic is the second most common histotype of pleural mesothelioma (PM). It shares epithelioid and sarcomatoid features and is challenging to diagnose. The aim of this study was to identify biphasic PM markers to improve subtyping and prognosis definition. The expression levels of 117 cancer genes, evaluated using the nanoString system, were compared between the three major histotypes (epithelioid, sarcomatoid, and biphasic), and expression differences within biphasic PM were evaluated in relation to the percentage of epithelioid components. Biphasic PM overexpressed CTNNA1 and TIMP3 in comparison to sarcomatoid, and COL16A1 and SDC1 in comparison to epithelioid PM. CFB, MSLN, CLDN15, SERPINE1, and PAK4 were deregulated among all histotypes, leading to the hypothesis of a gradual expression from epithelioid to sarcomatoid PM. According to gene expression, biphasic PM samples were divided in two clusters with a significant difference in the epithelioid component. ADCY4, COL1A1, and COL4A2 were overexpressed in the biphasic group with a low percentage of epithelioid component. Survival analysis using TCGA data showed that high COL1A1 and COL4A2 expression levels correlate with poor survival in PM patients. Herein, we identified markers with the potential to improve diagnosis and prognostic stratification of biphasic PM, which is still an orphan tumor. [ABSTRACT FROM AUTHOR]