•Uveal melanoma (UM) and malignant mesothelioma (MM) are BAP-TPDS core cancers.•Frequency of pathogenic germline variants in patients with MM is 1.8%.•This is comparable to the 1.9% frequency in ...Finnish patients with UM.•Finnish founder variant c.1780_1781insT is now found in five BAP1-TPDS families.•The role of recurring BINs in patients with BAP1-TPDS should be studied further.
Although asbestos exposure is the most common cause of malignant mesothelioma (MM), an aggressive cancer of the pleura or peritoneum, up to 7% of patients harbor a genetic predisposition to MM. Pathogenic germline variants in the BRCA1-associated protein 1 (BAP1) gene cause a dominantly inherited tumor predisposition syndrome, BAP1-TPDS, in which MM is the second most common associated cancer. Other frequent cancers in BAP1-TPDS are uveal melanoma (UM), cutaneous melanoma and renal cell carcinoma. Additionally patients can exhibit benign skin lesions, BAP1‐inactivated nevi (BIN). Most BINs arise sporadically, but patients with BAP1-TPDS may harbor multiple BINs before other tumors or as the only indication of the syndrome. Our objective was to establish the frequency of pathogenic germline BAP1 variants in Finnish patients with MM.
56 DNA samples archived in the Helsinki Biobank from Finnish patients with MM were sequenced for germline BAP1 variations. Formalin fixed paraffin embedded nevi from a pathogenic variant carrier were subjected to immunohistochemistry and exome sequencing.
Sanger sequencing identified one patient with Finnish founder mutation c.1780_1781insT, p.(G549Vfs*49) in BAP1. The carrier was diagnosed with MM over fifteen years before the cohorts mean onset age (mean 68, range 27 to 82) although the patient had no asbestos exposure or family history of BAP1-TPDS. However, the patient had three BINs removed prior to the MM. The c.1780_1781insT is now found from five Finnish BAP1-TPDS families with unknown common ancestor.
The frequency of pathogenic germline BAP1 variants in Finnish patients with MM is 1.8 % (95 % CI, 0.04 to 9.2), comparable to the frequency in Finnish patients with UM (1.9 %). The frequency of recurring BINs in patients with BAP1-TPDS should be studied further and genetic testing for BAP1 variants considered if the patient has ≥ 2 BAP1-TPDS core tumors, including BINs.
Background: Primary localized mediastinal mesothelioma is a rare tumour which accounts for about 0.7% of all mesotheliomas. The mesothelial cells lining of the pericardium are suggested as the most ...probable cells of origin. Mediastinal pleural mesothelioma are distinctly uncommon, which has only been reported in a single case. Case presentation: We report a case of a 57 years old man with primary mediastinal pleural mesothelioma involving middle and posterior upper mediastinum, one months following surgery, the patient is alive with good performance status. Chest plain scan and contrast-enhanced computer tomography（CT）scan showed a 43 mm×36 mm×36 mm tumor，with a CT value of about 41.5 HU, an arterial phase CT value of about 59.8HU and a venous phase CT value of about 77.5HU during the contrast-contrast-enhanced scan.Patients underwent thoracotomy.The pathological diagnosis was derived from malignant pleural mesothelioma(MPM) growing from the chest wall into the mediastinum. Conclusions Imaging manifestations of tumors have rarely been described in the literature. A short review of literature on MPM is given and summarize the imaging characteristics.
Malignant pleural mesothelioma (MPM) is an uncommon but aggressive and treatment resistant neoplasm with low survival rates. In the last years we assisted to an exponential growth in the appreciation ...of mesothelioma pathobiology, leading several new treatments to be investigated both in the early stage of the disease and in the advanced setting. In particular, expectations are now high that immunotherapy will have a leading role in the next years. However, caution is required as results from phase II studies in MPM were often not replicated in larger, randomized, phase III trials. In this review, we describe the most promising emerging therapies for the treatment of MPM, discussing the biological rationale underlying their development as well as the issues surrounding clinical trial design and proper selection of patients for every treatment.
Background
The distinction between mesothelioma with epithelioid features and metastatic carcinoma may be challenging, particularly on cytology. A novel 2‐hit Claudin‐4 and BRCA‐associated protein 1 ...(BAP1) panel was investigated.
Methods
The objective of this study was to determine the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the panel on cytology from pleural effusions and matched biopsies, including 49 malignant mesotheliomas on cytology with 43 matched biopsies, 49 normal/reactive mesothelial proliferations, and 49 pleural metastatic carcinomas from different primaries with 21 matched pleural biopsies. The diagnostic role of the 4 categories obtained by crossing the immunostaining results was analyzed.
Results
Claudin‐4 strongly stained all metastatic carcinomas and tested completely negative in normal mesothelium, benign reactive mesothelial hyperplasia, and malignant mesothelioma. All normal and benign mesothelial proliferations and all carcinomas except 1 were immunoreactive for BAP1, whereas BAP1 loss was observed in 88% of malignant mesotheliomas. The expression of Claudin‐4 alone excluded all benign and malignant mesothelial growth, consistently characterizing all metastatic carcinomas. Double negativity was evident in all malignant mesotheliomas, and double positivity was observed in all metastatic carcinomas. BAP1‐positive/Claudin‐4–negative status was observed only in malignant mesotheliomas and benign mesothelial proliferations. A single metastatic anal squamous cell carcinoma had BAP1‐negative/Claudin‐4–positive staining.
Conclusions
Claudin‐4 expression was completely specific and sensitive for metastatic carcinoma, excluding mesothelial proliferations. BAP1 staining characterized 98% of metastatic carcinomas and 100% of benign mesothelial proliferations, whereas negativity was observed almost exclusively in mesotheliomas. This 2‐hit panel is probably the best compromise for differentiating malignant mesothelioma and metastatic carcinoma on either cytology or biopsy specimens.
Claudin‐4 expression in effusion cytology is completely specific and sensitive for metastatic carcinoma, excluding mesothelial proliferations; otherwise, BRCA1‐associated protein 1 (BAP1) staining characterizes 98% of metastatic carcinomas and 100% of benign mesothelial proliferations, whereas negativity is almost exclusively disclosed in mesothelioma. This 2‐hit Claudin‐4/BAP1 panel is probably the best compromise in differentiating malignant mesothelioma and metastatic carcinoma on either cytology or biopsy specimens.
Diffuse malignant mesothelioma (MM) is an incurable tumour of the serosal membranes, which is often caused by exposure to asbestos and commonly diagnosed at advanced stage. Malignant mesothelioma in ...situ (MMIS) is now included as diagnostic category by the World Health Organization (WHO). However, our international survey of 34 pulmonary pathologists with an interest in MM diagnosis highlights inconsistency regarding how the diagnosis is being made by experts, despite published guidelines. Whilst the WHO restricts the diagnosis to surgical samples, the very concept has implication for cytological diagnosis, which is already regarded as controversial in itself by some. MMIS is currently only applicable as precursor to MM with an epithelioid component, and raises the possibility for different molecular pathways for different histological MM subtypes. The clinical implications of MMIS at this stage are uncertain, but aggressive therapies are being initiated in some instances. Based on the results of the survey we here present a critical appraisal of the concept, its clinical and conceptual implications and provide practice suggestions for diagnosis. A low threshold for ancillary testing is suggested. The designations of ‘malignant mesothelioma, cannot exclude MMIS’ or ‘atypical mesothelial proliferation with molecular indicators of malignancy, so-called MMIS’ could be used on cytology samples, adding ‘no evidence of invasion in sample provided’ for surgical samples. Clinical and radiological correlation are integral to diagnosis and best done at multidisciplinary meetings. Finally, collaborative studies are required to improve our understanding of MMIS.
Conventional measurements are not always helpful in the diagnosis of malignant mesothelioma (MM). Increasing studies indicate that loss of BRCA1-associated protein 1 (BAP1) detected by ...immunohistochemistry (IHC) is a useful diagnostic marker for MM. In this meta-analysis, we investigated the diagnostic accuracy of BAP1 in MM.
In total, 12 eligible studies with a total of 1824 patients were selected. Results indicated that loss of BAP1 sustained a pooled sensitivity of 0.56 (95% CI, 0.50-0.62), specificity of 1.00 (95% CI, 0.95-1.00), PLR of 548.82 (95% CI, 11.31-2.7 × 104), NLR of 0.44 (95% CI, 0.39-0.50), DOR of 1247.78 (95% CI, 25.08 -6.2 × 104) in discriminating MM from non-MM. The AUC of 0.72, reflecting the SROC, indicated moderate diagnostic accuracy. Subgroup analysis showed that BAP1 detection in histological specimens owned the higher diagnostic performance than cytological ones. In addition, BAP1 showed superior diagnostic accuracy in epithelioid MM than biphasic or sarcomatoid MM.
PubMed, Embase and the Cochrane Library and reference lists of related articles were searched, and studies that evaluated the utility of BAP1 in MM were included. Data from eligible studies were pooled to estimate sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR). Summary receiver operating curves (SROC) was applied to estimate overall diagnostic accuracy.
Current meta-analysis indicates that detection of BAP1 by IHC is a useful diagnostic marker for MM. Loss of BAP1 almost provides confirming diagnosis for MM, while positive staining for BAP1 is not enough to exclude non-MM.
Abstract
In this brief report, we described some uncommon cytomorphological features of malignant mesothelioma (MM) cells in pleural effusions. The tumor cells exhibited abundant cytoplasmic ...vacuolization, with presence of single or multiple eccentric nuclei in several cells. In the Giemsa‐stained smear, we observed a glossy spherical material in some cells, which tested positive in Sudan III stain. In immunocytochemical analysis, tumor cells were positive for calretinin, podoplanin, epithelial membrane antigen, and methylthioadenosine phosphorylase; tumor cells were negative for BRCA1‐associated protein 1, CD68, and desmin. The intracytoplasmic vacuoles were positive for adipophilin expression.
Background
The combination of immunobiological agents with immune checkpoint proteins is a promising treatment for malignant pleural mesothelioma (MPM). Mesothelin and anti-PD-L1 antibody-drug ...conjugates specifically target malignant neoplastic cells, inhibit the migration and invasion of neoplastic cells, and restore the immune landscape. In this study, we confirmed the importance of mesothelin and examined the relationship between mesothelin and the immune landscape of the tumor microenvironment (TME) in two MPM cohorts.
Methods
The discovery cohort included 82 MPM cases. Tissue microarray slides were generated, and samples were processed for hematoxylin & eosin staining, immunohistochemistry, and immunofluorescence assays. The relationship between mesothelin, biomarkers of histogenesis, histological aggressiveness, PD-L1, immune cells (CD4, CD8, CD20, CD68), and collagen type I and type V fibers was evaluated by quantitative digital analyses. The outcome was the survival time until death from disease recurrence. The exploratory cohort included 87 malignant mesothelioma (MESO) patients from The Cancer Genome Atlas database.
Results
Most patients were male (70.7%) with a history of asbestos exposure (53.7%) and with the epithelioid subtype (89%). Surgical resection was performed in 85.4% of patients, and 14.6% received chemotherapy; 59.8% of patients died from disease extension to the mediastinum. Low tumor mesothelin expression was associated with tumor necrosis and nuclear grade 1, whereas high mesothelin expression was significantly associated with the epithelioid histotype and high density of T cells CD8+, macrophages CD68+, and collagen type I fibers. Cox multivariate analysis showed a high risk of death for non-operated patients hazard ratio (HR), 3.42 (1.15–10.16) with low tumor mesothelin levels HR, 2.58 (1.09–6.10) and high PD-L1 and low infiltration of T cells CD4+ HR, 3.81 (1.58–9.18). In the exploratory cohort, low mesothelin and high COL1A1 and COL5A1 expression were associated with poor overall survival.
Conclusion
Tumor mesothelin expression associated with the TME immune landscape predicts the risk of death for patients with MPM and could be a new target for immunotherapy in MPM.
Objective To investigate the expression of peptidylarginine deiminase 2 and 4 (PAD2 and PAD4) in malignant mesothelioma (MM), their correlation with citrullinated proteins and clinical significance. ...Methods The pathological samples of 45 cases of MM in Zhejiang province from 2014 to 2021 were collected retrospectively for constructing paraffin-embedded tissue microarray. The expressions of PAD2 and PAD4 in tumor and paired adjacent tissues were detected by immunohistochemistry and the clinical significance was analyzed by utilizing bioinformatics database. Results The expressions of PAD2 and PAD4 in MM tissues were significantly higher than those in adjacent tissues (P<0.05). The protein expression of PAD2 and PAD4 was positively correlated with epithelial mesothelioma, peritoneal mesothelioma and pleural mesothelioma (P<0.05). There was a positive correlation between PAD2 and PAD4 mRNA transcription level (P<0.05). The expressions of PAD2 and PAD4 were positively correlated with citrullinated proteins, respe
Primary malignant mesothelioma of the liver is an extremely rare cancer, with only 16 cases reported in the literature so far. Diagnosis is challenging due to morphological similarity with common ...liver cancers and the extreme rarity of the condition.
We present the case of a 70-year-old man who was found to have an incidental liver mass which was diagnosed as primary malignant mesothelioma of the liver.
Our report describes the presentation of this rare liver malignancy and the challenges associated with diagnosis and treatment.
Primary malignant mesothelioma of the liver is an extremely rare condition.This diagnosis should be considered during the evaluation and treatment of a liver mass.
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