Biphasic Pleural Mesothelioma Research Articles

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

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.

Biphasic pleural mesothelioma treated successfully with multimodal therapy: a case report

BackgroundPleural mesothelioma is an aggressive malignant tumor and has a poor prognosis. In particular, biphasic pleural mesothelioma is a less common histologic type, and successful outcomes are rare.Case presentationA 60-year-old man was referred to our associated hospital because of dyspnea. Massive right pleural effusion and thickening of the entire right parietal pleura were revealed by radiological examination. After pleural biopsy, we diagnosed the patient’s tumor as biphasic pleural mesothelioma. The patient was admitted to our hospital for multimodal treatment. Two cycles of chemotherapy were initially administered with dramatic effects. Therefore, we decided to perform surgery and achieved a macroscopic complete resection. Postoperative chemotherapy was administered with no adverse events. No recurrence has been observed 11 months post-operation.ConclusionsWe encountered a case of biphasic pleural mesothelioma that responded well to chemotherapy, enabling macroscopic complete resection.

New Immunohistochemical Markers for Pleural Mesothelioma Subtyping.

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.

Gene Expression Analysis of Biphasic Pleural Mesothelioma: New Potential Diagnostic and Prognostic Markers.

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.

Differential Survival Characteristics of Sarcomatoid Subtype in Biphasic Pleural Mesothelioma

Biphasic pleural mesothelioma (BPM) accounts for approximately 10% of all pleural mesothelioma. Our aim was to assess the clinical, radiologic, and pathologic factors impacting survival in BPM and to better identify patients most likely to benefit from active treatment. A 10-year retrospective review was made of 214 biopsy-proven BPM cases with minimum 2-year follow-up. Patients with insufficient tissue for analysis were excluded (n= 96). Clinical and pathologic factors were evaluated along with radiologic assessment of pleural thickness. Survival was measured from time of diagnosis. Univariable and multivariable predictors of survival were evaluated. In all, 118 patients were included; 28 underwent pleurectomy/decortication, with 27 receiving additional modalities. Ninety patients underwent chemotherapy (n= 18) or radiotherapy alone (n= 9), 63 received combination therapy, and 27 received best supportive care. Median overall survival was 11.2 months (range, 0.3 to 36.2). At univariable analysis, pleurectomy/decortication (p= 0.0061), radiotherapy (p < 0.0001), and chemotherapy (p < 0.0001) were associated with superior survival when compared with best supportive care alone. Pleurectomy/decortication demonstrated 40% survival improvement compared with no surgery (p= 0.122). In a multivariable model, necrosis was negatively prognostic (hazard ratio 2.1, SE 0.76). Furthermore, increased sarcomatoid component was associated with worse survival without radiotherapy. BPM prognosis remains poor despite multimodality treatment. Anticancer treatment is associated with superior outcome in this nonrandomized retrospective series. Our findings suggest superior survival for patients with a lower proportion of sarcomatoid disease, with selective benefit of radiotherapy in higher proportions of sarcomatoid disease. When planning active treatment, the potential survival benefits require balancing against associated morbidity and recovery period.

Comparative proteomic analysis of malignant pleural mesothelioma: Focusing on the biphasic subtype

Malignant pleural mesothelioma (MPM) is a rare cancer originated from pleural mesothelial cells. MPM has been associated with long-term exposure to asbestos. In this work we performed a comparative proteomic analysis of biphasic pleural mesothelioma (B-PM).Tissue biopsies were obtained from 61 patients who were subjected to a diagnostic thoracoscopy. 2D/MS based approach was used for proteomic analysis. The 22 proteins found differentially expressed in B-PM, with respect to benign, were analyzed by Ingenuity Pathways Analysis and compared with those obtained for epitheliod pleural mesothelioma (E-PM). A different activation of transcription factors, proteins and cytokines were observed between two subtypes.

AB 57. Difficulties in biphasic mesothelioma diagnosis

Objective Presentation of a case of biphasic pleural mesothelioma with reference to difficulties concerning differential diagnosis from reactive mesothelial proliferations.

Therapeutic Surgery for Nonepithelioid Malignant Pleural Mesothelioma: Is it Really Worthwhile?

Debate remains about the relative prognostic importance of the histologic subtype of malignant pleural mesothelioma. From a prospective database, the details of 312 malignant pleural mesothelioma surgical patients were reviewed. A comparison was made of the survival from the three major cell types. One hundred ninety-five patients underwent radical surgery, and 117 underwent nonradical surgery. Final histologic subtype was epithelioid in 218 patients, biphasic in 66 patients, and sarcomatoid in 28 patients. The median survival was 15.3 months in the epithelioid group, 10.1 months in the biphasic group, and 5.0 months in the sarcomatoid group. On univariate analysis in the epithelioid group, age (p = 0.005), International Mesothelioma Interest Group stage (p = 0.001), radicality of the procedure (p = 0.001), leukocytosis (p = 0.016), and preoperative or postoperative chemotherapy (p = 0.012) were significant prognostic factors influencing postoperative survival. In the biphasic group, preoperative anemia was the only significant factor (p = 0.007). In sarcomatoid patients, International Mesothelioma Interest Group stage and radicality of the surgical procedure were significant prognostic variables (p = 0.012 and p = 0.015, respectively). Multivariate analysis in the epithelioid group identified International Mesothelioma Interest Group stage (p = 0.001), radicality of the procedure (p = 0.008), and preoperative or postoperative chemotherapy (p = 0.007) as significant prognostic factors, whereas in the sarcomatoid group, only the International Mesothelioma Interest Group stage (p = 0.012) was significant and the radicality of surgery had no effect. The extremely poor prognosis of sarcomatoid malignant pleural mesothelioma is independent of the extent of surgery unlike other cell types. Patients with sarcomatoid histology should therefore be considered separately in trials evaluating radical procedures and adjuvant treatment. The treatment of biphasic pleural mesothelioma remains debatable.

Malignant biphasic pleural mesothelioma metastatic to the liver diagnosed by fine-needle aspiration

As malignant pleural mesotheliomas are most often rapidly fatal, distant metastases are rarely detected. Here, we report a unique case in which the diagnosis of metastatic pleural mesothelioma was made via cytologic examination of a fine-needle aspiration (FNA) of the liver. Recognition of the cytomorphologic features inherent to mesothelioma cells on FNA material may become important for proper patient management. To the best of our knowledge, the diagnosis of malignant pleural mesothelioma metastatic to the liver made by FNA has not been previously documented.

Invasiveness of human pleural mesothelioma cells is influenced in vitro by the three-dimensional structure of the ECM and its composition

The grade of malignancy of a neoplasm is influenced by the invasive and metastatic potential of the tumor cells. The extracellular matrix of tissues is known to interact with many aspects of the biological behavior of tumor cells, such as differentiation and invasiveness. Therefore we studied the influence of the extracellular matrix on the morphology and invasiveness of the human biphasic pleural mesothelioma cell line MSTO-211H in vitro. The major components of the two strata encountered by a pleural mesothelioma cell leaving the epithelial community were mimicked by plating cells either on collagen I, the major component of the underlying stratum fibrosum, being encountered by cells under pathological conditions or on reconstituted basement membrane (Matrigel) in order to simulate the basement membrane of the stratum serosum of the mesothelium, which is the matrix cells have contact to under physiological conditions. Growth on collagen I leads to cell separation and invasion into the matrix, whereas growth of MSTO-211H cells on Matrigel results in the formation of a huge and dense network of cells extending throughout the whole plating area. The morphology of cell contacts between the two populations varies impressively. While cells on collagen I hardly find to each other in groups, and if so, with a broad intercellular cleft, Matrigel induces the tight approach of membranes of neighbouring cells with formation of syncytium-like structures. Administration of the main ECM components laminin and collagen IV alone and together in equimolar concentrations as present in Matrigel, does not result in any morphological changes when compared to cells growing on plastic substrates or on collagen I. Therefore, collagen I increases cell separation and invasiveness whereas an intact basement membrane seems to prevent the cells from separating and spreading, thus lowering their invasive potential.