Identifying malignant mesothelioma by a pathological survey using the São Paulo state hospital cancer registry, Brazil.

OBJECTIVE: To review the pathological diagnosis of possible cases and/or hidden cases of malignant mesothelioma (MM) between 2000 and 2012 using the Hospital-Based Cancer Registry database in the state of São Paulo, Brazil. METHODS: Possible cases were retrieved by assessing the database. Inclusion criteria were being older than 30 years of age and having ICD-O-3 topography and morphology codes related to MM. A board of expert pathologists reviewed the pathology reports and requested paraffin blocks in cases that demanded revision. After staining with calretinin, D2-40, WT-1 (as positive MM markers) and Ber-EP4 and MOC31 (as negative MM markers), cases were divided and studied independently by a pair of pathologists to confirm or discard the diagnosis of MM. RESULTS: Our sample comprised 482 cases from 25 hospitals, and 130 needed further histological revision. We received 73 paraffin blocks with adequate material. After board analysis, there were 9 cases with a definitive diagnosis of MM, improving the diagnostic rate in 12%. Two cases of previously diagnosed MM were discarded by review. CONCLUSIONS: Our results confirm that part of MM underdiagnosis and underreporting in Brazil is due to incomplete or mistaken pathological diagnosis.

Mesothelioma-Associated Fibroblasts Modulate the Response of Mesothelioma Patient-Derived Organoids to Chemotherapy via Interleukin-6.

Malignant pleural mesothelioma (MPM) remains an incurable disease. This is partly due to the lack of experimental models that fully recapitulate the complexity and heterogeneity of MPM, a major challenge for therapeutic management of the disease. In addition, the contribution of the MPM microenvironment is relevant for the adaptive response to therapy. We established mesothelioma patient-derived organoid (mPDO) cultures from MPM pleural effusions and tested their response to pemetrexed and cisplatin. We aimed to evaluate the contribution of mesothelioma-associated fibroblasts (MAFs) to the response to pemetrexed and cisplatin (P+C). Organoid cultures were obtained from eight MPM patients using specific growth media and conditions to expand pleural effusion-derived cells. Flow cytometry was used to verify the similarity of the organoid cultures to the original samples. MAFs were isolated and co-cultured with mPDOs, and the addition of MAFs reduced the sensitivity of mPDOs to P+C. Organoid formation and expression of cancer stem cell markers such as ABCG2, NANOG, and CD44 were altered by conditioned media from treated MAFs. We identified IL-6 as the major contributor to the attenuated response to chemotherapy. IL-6 secretion by MAFs is correlated with increased resistance of mPDOs to pemetrexed and cisplatin.

Pleural mesothelioma from fluoro-edenite exposure: PACAP and PAC1 receptor. A preliminary report.

Pleural mesothelioma is a devastating malignancy primarily associated with asbestos exposure. However, emerging evidence suggests that exposure to fluoro-edenite fibers, a naturally occurring mineral fiber, can also lead to the development of pleural mesothelioma. In this study, based on the hypothesis that pituitary adenylate cyclase-activating polypeptide (PACAP) and PACAP-preferring receptor (PAC1R) expressions could be dysregulated in pleural mesothelioma samples and that they could potentially act as diagnostic or prognostic biomarkers, we aimed to investigate the immunohistochemical expression of PACAP and PAC1R in pleural biopsies from patients with pleural mesothelioma exposed to fluoro-edenite fibers. A total of 12 patients were included in this study, and their biopsies were processed for immunohistochemical analysis to evaluate the expression of PACAP and its receptor. The study revealed a correlation between the overexpression of PACAP and PAC1R and shorter overall survival in patients with malignant mesothelioma. These findings suggest that PACAP and PAC1R expression levels could serve as potential prognostic biomarkers for malignant mesothelioma. Furthermore, the immunohistochemical analysis of PACAP and PAC1R may provide valuable information for clinicians to guide therapeutic decisions and identify patients with poorer prognosis.

FK228 suppress the growth of human malignant pleural mesothelioma tumor independent to epithelioid or non-epithelioid histology.

Human malignant pleural mesothelioma (hMPM) is an aggressive, rare disease with a poor prognosis. Histologically, MPM is categorized into epithelioid, biphasic, and sarcomatoid subtypes, with the epithelioid subtype generally displaying a better response to treatment. Conversely, effective therapies for the non-epithelioid subtypes are limited. This study aimed to investigate the potential role of FK228, a histone deacetylase inhibitor, in the suppression of hMPM tumor growth. We conducted a comprehensive analysis of the histological and molecular characteristics of two MPM cell lines, CRL-5820 (epithelioid) and CRL-5946 (non-epithelioid). CRL-5946 cells and non-epithelioid patient-derived xenografted mice exhibited heightened growth rates compared to those with epithelioid MPM. Both CRL-5946 cells and non-epithelioid mice displayed a poor response to cisplatin. However, FK228 markedly inhibited the growth of both epithelioid and non-epithelioid tumor cells in vitro and in vivo. Cell cycle analysis revealed FK228-induced G1/S and mitotic arrest in MPM cells. Caspase inhibitor experiments demonstrated that FK228-triggered apoptosis occurred via a caspase-dependent pathway in CRL-5946 but not in CRL-5820 cells. Additionally, a cytokine array analysis showed that FK228 reduced the release of growth factors, including platelet-derived and vascular endothelial growth factors, specifically in CRL-5946 cells. These results indicate that FK228 exhibits therapeutic potential in MPM by inducing cytotoxicity and modulating the tumor microenvironment, potentially benefiting both epithelioid and non-epithelioid subtypes.

Linc00941 fuels ribogenesis and protein synthesis by supporting robust cMYC translation in malignant pleural mesothelioma.

Malignant pleural mesothelioma is a rare and lethal cancer caused by exposure to asbestos. The highly inflammatory environment caused by fibers accumulation forces cells to undergo profound adaptation to gain survival advantages. Prioritizing the synthesis of essential transcripts is an efficient mechanism coordinated by multiple molecules, including long non-coding RNAs. Enhancing the knowledge about these mechanisms is an essential weapon in combating mesothelioma. Linc00941 correlates to bad prognosis in various cancers, but it is reported to partake in distinct and apparently irreconcilable processes. In this work, we report that linc00941 supports the survival and aggressiveness of mesothelioma cells by influencing protein synthesis and ribosome biogenesis. Linc00941 binds to the translation initiation factor eIF4G, promoting the selective protein synthesis of cMYC, which, in turn, enhances the expression of key genes involved in translation. We analyzed a retrospective cohort of 97 mesothelioma patients' samples from our institution, revealing that linc00941 expression strongly correlates with reduced survival probability. This discovery clarifies linc00941's role in mesothelioma and proposes a unified mechanism of action for this lncRNA involving the selective translation of essential oncogenes, reconciling the discrepancies about its function.

Prognostic significance of inflammation scores in malignant mesothelioma.

OBJECTIVE: The relationship between inflammatory markers and survival in many cancers has been investigated previously. Inflammatory markers may also offer the possibility of predicting surveillance in patients with malignant mesothelioma. Our study seeks to enhance comprehension of how variables such as the nutritional status and inflammation indices of malignant mesothelioma patients impact the disease's progression and prognosis. PATIENTS AND METHODS: This study included patients who were treated at the Erciyes University Medical Oncology Clinic between 2010 and 2022 and diagnosed with malignant mesothelioma. This is a retrospective single-center cohort study. Receiver Operating Characteristic (ROC) analysis was applied to determine the inflammation markers' optimal cut-off values with high sensitivity and specificity. Patients were categorized based on these values. The differences in overall survival (OS) and progression-free survival (PFS) between categorized groups were assessed using Log-rank curves and Kaplan-Meier tests. Multivariate analysis was performed using Cox regression analysis on statistically significant data. The relationship between inflammation markers and malignant mesothelioma survival was evaluated. RESULTS: There are 115 patients in this study. Pre-treatment high neutrophil to lymphocyte ratio (NLR) (HR: 1.34, 95% CI: 1.12-2.83, p=0.04), high pan-immune inflammation value (PIIV) (HR: 2.01, 95% CI: 1.32-4.79, p=0.03), and high systemic inflammation response index (SIRI) (HR: 1.34, 95% CI: 1.2-2.78, p=0.04) were associated with poor OS. Conversely, high advanced lung cancer inflammation index (ALI) (HR: 0.73, 95% CI: 0.53-0.84, p=0.03) and high hemoglobin-albumin-lymphocyte and platelet (HALP) (HR: 0.67, 95% CI: 0.23-0.78, p=0.02) were associated with favorable survival. CONCLUSIONS: Our study investigated the prognostic value of various inflammation markers in malignant mesothelioma patients and suggests that composite formulas like NLR, PIIV, SIRI, ALI, and HALP that incorporate CBC cells and nutritional parameters like albumin, height, and weight could more consistently and accurately predict malignant mesothelioma prognosis.

Evaluation of first-line and salvage therapies for unresectable malignant mesothelioma: A systematic review and network meta-analysis.

BACKGROUND: Randomized controlled trials (RCTs) of systemic therapies for unresectable malignant mesothelioma have reported conflicting results. It is crucial and urgent to find optimal treatment options for this malignancy, which currently has a poor prognosis. METHODS: Databases PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, and major international conferences were searched until February 29, 2024. The main outcomes of interest were overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and grade ≥3 treatment-related adverse events (TRAEs). RESULTS: We analyzed 16 RCTs with a total of 5018 patients. Among first-line therapies, nivolumab and ipilimumab significantly increased OS and resulted in fewer grade ≥3 TRAEs. Bevacizumab plus chemotherapy significantly increased PFS. Among salvage therapies, ramucirumab and chemotherapy was associated with the best OS and PFS, but resulted in more grade ≥3 TRAEs. Subgroup analysis by histologic types suggested that in first-line settings, bevacizumab and chemotherapy increase OS the most for epithelioid type, while the nivolumab plus ipilimumab treatment increases OS the most for non-epithelioid type. In salvage therapies, ramucirumab and chemotherapy increase OS for both epithelioid and non-epithelioid types. CONCLUSION: Nivolumab plus ipilimumab was associated with the best OS among first-line treatments. Ramucirumab and chemotherapy was associated with the best clinical outcomes in salvage settings. Treatment for malignant mesothelioma should be tailored based on different clinicopathological characteristics.

Diagnosis and treatment of malignant retroperitoneal mesothelioma: A case report.

RATIONALE: Malignant peritoneal mesothelioma (MPM) is a rare clinical disease. Although there are several reports describing intraperitoneal mesothelioma of the lung, liver, and intestine, retroperitoneal mesothelioma is, to our knowledge, very rare and rarely reported. In recent years, our best clinical protocols for the treatment and diagnosis of retroperitoneal mesothelioma have not been proven and the diagnosis and treatment are challenging. PATIENT CONCERNS: A 37-year-old Chinese woman complained of bilateral low back pain for a month, with obvious symptoms of low back pain on the left side. To treat low back pain, retroperitoneal masses were found during physical examination. The patient consulted a urological specialist for further treatment. DIAGNOSIS: After the operation, pathological biopsy confirmed retroperitoneal epithelioid diffuse mesothelioma. INTERVENTIONS: After exclusion of surgical contraindications, the patient underwent laparoscopic retroperitoneal lesion resection under tracheal intubation and general anesthesia, and the operation was successful. OUTCOMES: On the tenth day after surgery, the patient vital signs were stable, and he was discharged. LESSONS: Patients with malignant peritoneal mesothelioma may have no typical clinical symptoms, and the diagnosis is based on pathological and immunohistochemical examination. In selected patients, surgical cell reduction and intraoperative intraperitoneal heat chemotherapy have become the first choice of treatment, which can achieve ideal therapeutic effects and prolong survival.

Diagnostic performance of immunohistochemistry markers for malignant pleural mesothelioma diagnosis and subtypes. A systematic review and meta-analysis.

BACKGROUND: Malignant pleural mesothelioma (MPM) poses diagnostic challenges due to its resemblance to benign pleural pathologies and different histological subtypes. Several immunohistochemistry markers have been employed to aid in accurate diagnosis. METHODS: The present systematic review and meta-analysis aimed to assess the diagnostic performance of various immunohistochemistry markers in malignant pleural mesothelioma diagnosis and its histological subtypes. Following the PRISMA guidelines, we systematically searched the literature for articles on using different immunohistochemical markers in MPM and its histological subtypes. EMBASE, LILACS, MEDLINE, and Virtual Health Library were searched for studies published up to August 2023. We used the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies) criteria to assess the quality of the included articles. Meta-analyses were performed to determine prevalence using a random-effects model. RESULTS: 103 studies met the inclusion criteria, comprising a diverse range of immunohistochemistry markers. EMA and desmin-loss exhibited high sensitivity (96% and 92%, respectively) in distinguishing malignant pleural mesothelioma from benign pleural pathologies. Specificity was notably high for both BAP1-loss and survivin expression at 100%. Subtype-specific analyses demonstrated that EMA and HEG1 were sensitive markers for epithelioid mesothelioma, while GLUT1 showed high sensitivity for sarcomatoid mesothelioma. In cases comparing epithelioid mesothelioma and lung adenocarcinoma, CAM5.2 and calretinin displayed high sensitivity, while WT1 and BAP1-loss demonstrated exceptional specificity for malignant epithelioid mesothelioma. In the case of sarcomatoid mesothelioma and sarcomatoid lung carcinoma, GATA3 exhibited the most heightened sensitivity, while GATA3 and D2-40 displayed the best specificity for sarcomatoid malignant mesothelioma diagnosis. CONCLUSION: Immunohistochemistry markers are essential in accurately diagnosing malignant pleural mesothelioma and its histological subtypes. This systematic review and meta-analysis provide a comprehensive insight into the diagnostic performance of these markers, facilitating their potential clinical utility in the discrimination of malignant pleural mesothelioma from other pleural pathologies and the differentiation of malignant pleural mesothelioma subtypes.

Circulating SMRP and CA-125 before and after pleurectomy decortication for pleural mesothelioma.

BACKGROUND: Tumor recurrence remains the main barrier to survival after surgery for pleural mesothelioma (PM). Soluble mesothelin-related protein (SMRP) and cancer antigen 125 (CA-125) are established blood-based biomarkers for monitoring PM. We prospectively studied the utility of these biomarkers after pleurectomy decortication (PD). METHODS: Patients who underwent PD and achieved complete macroscopic resection with available preoperative SMRP levels were included. Tumor marker levels were determined within 60 days of three timepoints: (1) preoperation, (2) post-operation, and (3) recurrence. RESULTS: Of 356 evaluable patients, 276 (78%) had recurrence by the end of follow-up interval. Elevated preoperative SMRP levels were associated with epithelioid histology (p < 0.013), advanced TNM (p < 0.001) stage, and clinical stage (p < 0.001). Preoperative CA-125 levels were not significantly associated with clinical covariates. Neither biomarker was associated with survival or disease-free survival. With respect to nonpleural and nonlymphatic recurrences, mean SMRP levels were elevated in patients with pleural (p = 0.021) and lymph node (p = 0.042) recurrences. CA-125 levels were significantly higher in patients with abdominal (p < 0.001) and lymph node (p = 0.004) recurrences. Among patients with all three timepoints available, we observed an average decrease in SMRP levels by 1.93 nmol/L (p < 0.001) postoperatively and again an average increase at recurrence by 0.79 nmol/L (p < 0.001). There were no significant changes in levels of CA-125 across the study timepoints (p = 0.47). CONCLUSIONS: Longitudinal changes in SMRP levels corresponded with a radiographic presence of disease in a subset of patients. SMRP surveillance could aid in detection of local recurrences, whereas CA-125 could be helpful in recognizing abdominal recurrences.

Identification of the ferroptosis-related prognostic gene signature in mesothelioma.

Mesothelioma, an uncommon yet highly aggressive malignant neoplasm, presents challenges in the effectiveness of current therapeutic approaches. Ferroptosis, a non-apoptotic mechanism of cellular demise, exhibits a substantial association with the progression of diverse cancer forms. It is important to acknowledge that there exists a significant association between ferroptosis and the advancement of various forms of cancer. Nevertheless, the precise role of ferroptosis regulatory factors within the context of mesothelioma remains enigmatic. In our investigation, we initially scrutinized the prognostic significance of 24 ferroptosis regulatory factors in the realm of mesothelioma. Our observations unveiled that heightened expression levels of CARS1, CDKN1A, TFRC, FANCD2, FDFT1, HSPB1, SLC1A5, SLC7A11, coupled with reduced DPP4 expression, were indicative of an unfavorable prognosis. Built upon the nine previously discussed prognostic genes, the ferroptosis prognostic model offers a reliable means to forecast mesothelioma patients' survival with a substantial degree of precision. Furthermore, a notable correlation emerged between these prognostic ferroptosis regulators and parameters such as immune cell infiltration, tumor mutation burden, microsatellite instability, and PD-L1 expression in the context of mesothelioma. Within this cadre of nine ferroptosis regulatory factors with prognostic relevance, FANCD2 exhibited the most pronounced prognostic influence, as elucidated by our analyses. Subsequently, we executed a validation process employing clinical specimens sourced from our institution, thus confirming that heightened FANCD2 expression is a discernible harbinger of an adverse prognosis in the context of mesothelioma. In vitro experiments revealed that knocking down FANCD2 markedly suppressed the proliferation, migration, and ability of mesothelioma cells to attract immune cells. Furthermore, our findings also showed that reducing FANCD2 levels heightened the vulnerability of mesothelioma cells to inducers of ferroptosis. Furthermore, an extensive pan-cancer analysis uncovered a robust association between FANCD2 and the gene expression linked to immune checkpoints, thereby signifying an adverse prognosis across a broad spectrum of cancer types. Additional research is warranted to validate these findings.

Establishing mesothelioma patient-derived organoid models from malignant pleural effusions.

OBJECTIVES: Pleural mesothelioma is a cancer arising in the cells that line the lungs and chest wall with poor survival and poor response to first-line therapy. Organoid models of cancer can faithfully recapitulate the genetic and histopathological characteristics of individualized tumors and have potential to be used for precision medicine, however methods of establishing patient-derived mesothelioma organoids have not been well established in the published literature. MATERIALS AND METHODS: Long-term mesothelioma patient-derived organoids were established from ten malignant pleural effusion fluids. Mesothelioma patient-derived organoids were compared to the corresponding biopsy tissue specimens using immunohistochemistry labelling for select diagnostic markers and the TruSight Oncology-500 sequencing assay. Cell viability in response to the chemotherapeutic drug cisplatin was assessed. RESULTS: We established five mesothelioma patient-derived organoid cultures from ten malignant pleural effusion fluids collected from nine individuals with pleural mesothelioma. Mesothelioma patient-derived organoids typically reflected the histopathological and genomic features of patients' matched biopsy specimens and displayed cytotoxic sensitivity to cisplatin in vitro. CONCLUSION: This is the first study of its kind to establish long-term mesothelioma organoid cultures from malignant pleural effusions and report on their utility to test individuals' chemotherapeutic sensitivities ex vivo.

Reliably making the primary diagnosis of mesothelioma utilizing serous fluid cytology specimens: an institutional experience.

INTRODUCTION: The diagnosis of mesothelioma has historically been challenging, especially on serous fluid cytology (SFC). Distinguishing between reactive and neoplastic mesothelial cells can be difficult on cytomorphology alone. However, additional ancillary tests, such as BRCA1 associated protein-1 immunohistochemistry and fluorescence in situ hybridization for cyclin-dependent kinase inhibitor 2A deletion, can provide a sensitive and highly specific method of proving malignancy. MATERIALS AND METHODS: SFC specimens diagnosed as mesothelioma, suspicious for mesothelioma (SM), and atypical mesothelial cells (AMCs) since 2012 were identified by querying the laboratory information system. Clinical data and pathologic parameters were gathered. RESULTS: One hundred ten cases of mesothelioma, SM, and AMC were identified. Of these, 61 cases had a definitive diagnosis of mesothelioma on SFC. Average age at SFC diagnosis was 67 years (26-87 years), with most patients being male (67%). Out of the 61 cases, 11 cases (18%) had an initial diagnosis of mesothelioma made on SFC specimens, with 5 of these 11 cases being in patients that never received a histologic diagnosis of mesothelioma. Ancillary studies were utilized in all 11 cases. An initial diagnosis of metastatic mesothelioma was made on SFC in 9 cases (15%). For 6 of these 9 cases, the SFC diagnosis was the sole diagnosis of metastatic mesothelioma without a companion histologic diagnosis. In addition, 15 cases were diagnosed as SM, with 11 of these cases following a definitive mesothelioma diagnosis. Thirty-four cases were diagnosed as AMC, with 27 cases following a definitive mesothelioma diagnosis. CONCLUSIONS: The diagnosis of mesothelioma can be reliably made on SFC with the appropriate cytomorphology criteria and/or confirmatory ancillary testing.

Mesothelioma of the tunica vaginalis testis.

Mesothelioma of the tunica vaginalis testis (MTVT) is a rare tumour and a cause of hydrocele. This case report concerns a 26-year-old male with hydrocele treated with left hydrocelectomy. Histopathology revealed MTVT, and left radical orchiectomy was performed followed by chemotherapy. Fluorescence in situ hybridization, DNA and RNA next-generation sequencing showed no mesothelioma-associated tumour suppressor gene mutations, but deletion of CDKN2A and a rare TFG-ADGRG7 fusion both reported in pleural mesotheliomas, were detected. Clinicians should consider malignancy in case of discrepancy between symptoms and objective findings in scrotal conditions.

Pediatric, Adolescent and Young Adult (AYA) Peritoneal and Pleural Mesothelioma: A National Cancer Database Review.

PURPOSE: Malignant peritoneal and pleural mesothelioma are rare in young patients, with a paucity of data regarding clinical characteristics and outcomes. We aimed to describe the clinical characteristics, treatment strategies, and outcomes for pediatric and adolescent/young adult (AYA) patients. METHODS: The National Cancer Database (NCDB) was queried for malignant peritoneal and pleural mesothelioma in pediatric and AYA patients (ages 0-39) from 2004 to 2019. Stratification was performed for pediatric (age 0-21) and young adult (age 22-39) patients. Chi-squared, multivariable cox regression, and Kaplan-Meier analyses were performed. RESULTS: We identified 570 total patients, 46 pediatric and 524 young adult, with mesothelioma (363 peritoneal and 207 pleural). There were significant differences in sex distribution as patients with peritoneal mesothelioma were more frequently female (63.1%). Patients with peritoneal mesothelioma were more likely to have radical surgery compared to pleural mesothelioma (56.7% v. 24.6%, respectively). A majority of patients with peritoneal and pleural mesothelioma received chemotherapy (66.4% and 61.4%, respectively). For peritoneal mesothelioma, surgical resection was associated with improved overall survival, whereas male sex, neoadjuvant chemotherapy, and radiation were associated with worse overall survival. For pleural mesothelioma, intraoperative chemotherapy was associated with improved overall survival, whereas Black race was associated with worse overall survival. Mean overall survival was greater for patients with peritoneal mesothelioma (125 months) compared to those with pleural mesothelioma (69 months), which remained significant after stratification of pediatric and young adult patients. CONCLUSION: By analyzing a large cohort of pediatric and AYA mesothelioma, this study highlights clinical, prognostic, and survival differences between peritoneal and pleural disease. LEVEL OF EVIDENCE: Level III. TYPE OF STUDY: Retrospective.

Single-cell transcriptomic analysis of human pleura reveals stromal heterogeneity and informs in vitro models of mesothelioma.

The pleural lining of the thorax regulates local immunity, inflammation and repair. A variety of conditions, both benign and malignant, including pleural mesothelioma, can affect this tissue. A lack of knowledge concerning the mesothelial and stromal cells comprising the pleura has hampered the development of targeted therapies. Here, we present the first comprehensive single-cell transcriptomic atlas of the human parietal pleura and demonstrate its utility in elucidating pleural biology. We confirm the presence of known universal fibroblasts and describe novel, potentially pleural-specific, fibroblast subtypes. We also present transcriptomic characterisation of multiple in vitro models of benign and malignant mesothelial cells, and characterise these through comparison with in vivo transcriptomic data. While bulk pleural transcriptomes have been reported previously, this is the first study to provide resolution at the single-cell level. We expect our pleural cell atlas will prove invaluable to those studying pleural biology and disease. It has already enabled us to shed light on the transdifferentiation of mesothelial cells, allowing us to develop a simple method for prolonging mesothelial cell differentiation in vitro.

Molecular and Immunohistochemical Testing in Mesothelioma and Other Mesothelial Lesions.

CONTEXT.­: Molecular testing has increasingly been utilized in the evaluation of mesothelioma. Diffuse mesothelioma comprises multiple distinct genetic subgroups. While most diffuse mesotheliomas lack oncogenic kinase mutations and instead harbor alterations involving tumor suppressors and chromatin regulators, a minor subset of tumors is characterized by uncommon alterations such as germline mutations, genomic near-haploidization, ALK rearrangement, ATF1 rearrangement, or EWSR1::YY1 fusion. OBJECTIVE.­: To provide updates on the salient molecular features of diffuse mesothelioma, mesothelioma in situ, and other mesothelial lesions: well-differentiated papillary mesothelial tumor, adenomatoid tumor, peritoneal inclusion cyst, and others. We consider the diagnostic, prognostic, and predictive utility of molecular testing in mesothelial lesions. DATA SOURCES.­: We performed a literature review of recently described genetic features, molecular approaches, and immunohistochemical tools, including BAP1, MTAP, and merlin in mesothelioma and other mesothelial lesions. CONCLUSIONS.­: Our evolving understanding of the molecular diversity of diffuse mesothelioma and other mesothelial lesions has led to considerable changes in pathology diagnostic practice, including the application of immunohistochemical markers such as BAP1, MTAP, and merlin (NF2), which are surrogates of mutation status. In young patients and/or those without significant asbestos exposure, unusual mesothelioma genetics such as germline mutations, ALK rearrangement, and ATF1 rearrangement should be considered.

Asbestos burden in lungs of mesothelioma patients with pleural plaques, lung fibrosis and/or ferruginous bodies at histology: a postmortem SEM-EDS study.

The causal attribution of asbestos-related diseases to past asbestos exposures is of crucial importance in clinical and legal contexts. Often this evaluation is made based on the history of exposure, but this method presents important limitations. To assess past asbestos exposure, pleural plaques (PP), lung fibrosis and histological evidence of ferruginous bodies (FB) can be used in combination with anamnestic data. However, such markers have never been associated with a threshold value of inhaled asbestos. With this study we attempted to shed light on the dose-response relationship of PP, lung fibrosis and FBs, investigating if their prevalence in exposed individuals who died from malignant mesothelioma (MM) is related to the concentration of asbestos in lungs assessed using scanning electron microscopy equipped with energy dispersive spectroscopy. Moreover, we estimated the values of asbestos concentration in lungs associated with PP, lung fibrosis and FB. Lung fibrosis showed a significant positive relationship with asbestos lung content, whereas PP and FB did not. We identified, for the first time, critical lung concentrations of asbestos related to the presence of PP, lung fibrosis and FB at histology (respectively, 19 800, 26 400 and 27 400 fibers per gram of dry weight), that were all well-below the background levels of asbestos identified in our laboratory. Such data suggest that PP, lung fibrosis and FB at histology should be used with caution in the causal attribution of MM to past asbestos exposures, while evaluation of amphibole lung content using analytical electron microscopy should be preferred.