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European Respiratory Review : An... Mar 2021Malignant pleural mesothelioma is an aggressive, incurable cancer that is usually caused by asbestos exposure several decades before symptoms arise. Despite widespread... (Review)
Review
Malignant pleural mesothelioma is an aggressive, incurable cancer that is usually caused by asbestos exposure several decades before symptoms arise. Despite widespread prohibition of asbestos production and supply, its incidence continues to increase. It is heterogeneous in its presentation and behaviour, and diagnosis can be notoriously difficult. Identification of actionable gene mutations has proven challenging and current treatment options are largely ineffective, with a median survival of 10-12 months.However, the past few years have witnessed major advances in our understanding of the biology and pathogenesis of mesothelioma. This has also revealed the limitations of existing diagnostic algorithms and identified new treatment targets.Recent clinical trials have re-examined the role of surgery, provided new options for the management of associated pleural effusions and heralded the addition of targeted therapies. The increasing complexity of mesothelioma management, along with a desperate need for further research, means that a multidisciplinary team framework is essential for the delivery of contemporary mesothelioma care.This review provides a synthesised overview of the current state of knowledge and an update on the latest research in the field.
Topics: Asbestos; Biology; Humans; Mesothelioma; Mesothelioma, Malignant; Pleural Neoplasms
PubMed: 33472960
DOI: 10.1183/16000617.0226-2020 -
Modern Pathology : An Official Journal... Jan 2022We report nine examples of a previously undescribed type of peritoneal circumscribed nodular mesothelial tumor characterized by nests or sheets of mesothelial cells with...
We report nine examples of a previously undescribed type of peritoneal circumscribed nodular mesothelial tumor characterized by nests or sheets of mesothelial cells with sharp cell borders and extremely bland, sometimes grooved, nuclei. In some cases, nests were separated by fibrous bands. All patients were women, age range 30-72 years (median 52 years). All tumors were incidental findings during surgery and grossly were either solitary nodules or a few small nodules on the peritoneal surface. Referring pathologic diagnoses included diffuse malignant mesothelioma, localized malignant mesothelioma, well-differentiated papillary mesothelioma, and adenomatoid tumor. No tumor showed BAP1 loss by immunohistochemistry nor deletion of CDKN2A by FISH. RNA-seq revealed that these tumors clustered together and were distinct from peritoneal diffuse malignant mesotheliomas. Very few mutations or translocations were found, none of them recurrent from tumor to tumor, and no tumor showed an abnormality in any of the genes typically mutated/deleted in diffuse malignant mesothelioma. Array CGH on three cases revealed two with a completely flat profile and one with a small deletion at 3q26-3q28. On follow-up (range 5-60, median 34 months), there were no deaths, no recurrences, and no evidence of metastatic disease nor local spread; one case that initially had scattered nodules on the pelvic peritoneum had the same pattern of nodules at a second look operation 2 years later. We propose the name solid papillary mesothelial tumor for these lesions. These appear to be either benign or very low-grade tumors that need to be separated from malignant mesotheliomas.
Topics: Adult; Aged; Carcinoma, Papillary; Chi-Square Distribution; Cluster Analysis; Cohort Studies; Female; Follow-Up Studies; Gene Expression Regulation, Neoplastic; Humans; In Situ Hybridization, Fluorescence; Incidental Findings; Middle Aged; Mutation; Neoplasms, Mesothelial; Peritoneal Neoplasms; Prognosis; Sequence Analysis, RNA; Signal Transduction; Time Factors; Translocation, Genetic
PubMed: 34480081
DOI: 10.1038/s41379-021-00899-3 -
Cancer Genomics & Proteomics 2023Mesotheliomas are tumors similar to, and probably derived from, mesothelial cells. They carry acquired chromosomal rearrangements, deletions affecting CDKN2A,...
BACKGROUND/AIM
Mesotheliomas are tumors similar to, and probably derived from, mesothelial cells. They carry acquired chromosomal rearrangements, deletions affecting CDKN2A, pathogenetic polymorphisms in NF2, and fusion genes which often contain the promiscuous EWSR1, FUS, and ALK as partner genes. Here, we report the cytogenomic results on two peritoneal mesotheliomas.
MATERIALS AND METHODS
Both tumors were examined using G-banding with karyotyping and array comparative genomic hybridization (aCGH). One of them was further investigated with RNA sequencing, reverse transcription polymerase chain reaction (RT-PCR), Sanger sequencing, and fluorescence in situ hybridization (FISH).
RESULTS
In the first mesothelioma, the karyotype was 25∼26,X,+5,+7,+20[cp4]/50∼52,idemx2[cp7]/46,XX[2]. aCGH detected gains of chromosomes 5, 7, and 20 with retained heterozygosity on these chromosomes. In the second tumor, the karyotype was 46,XX,inv(10)(p11q25)[7]/46,XX[3]. aCGH did not detect any gains or losses and showed heterozygosity for all chromosomes. RNA sequencing, RT-PCR/Sanger sequencing, and FISH showed that the inv(10) fused MAP3K8 from 10p11 with ABLIM1 from 10q25. The MAP3K8::ABLIM1 chimera lacked exon 9 of MAP3K8.
CONCLUSION
Our data, together with information on previously described mesotheliomas, illustrate two pathogenetic mechanisms in peritoneal mesothelioma: One pathway is characterized by hyperhaploidy, but with retained disomies for chromosomes 5, 7, and 20; this may be particularly prevalent in biphasic mesotheliomas. The second pathway is characterized by rearrangements of MAP3K8 from which exon 9 of MAP3K8 is lost. The absence of exon 9 from oncogenetically rearranged MAP3K8 is a common theme in thyroid carcinoma, lung cancer, and spitzoid as well as other melanoma subtypes.
Topics: Humans; In Situ Hybridization, Fluorescence; Comparative Genomic Hybridization; Mesothelioma, Malignant; Mesothelioma; Carcinogenesis; Cell Transformation, Neoplastic; Peritoneal Neoplasms; Microfilament Proteins; LIM Domain Proteins
PubMed: 37400148
DOI: 10.21873/cgp.20388 -
Orphanet Journal of Rare Diseases Dec 2008Malignant mesothelioma is a fatal asbestos-associated malignancy originating from the lining cells (mesothelium) of the pleural and peritoneal cavities, as well as the... (Review)
Review
Malignant mesothelioma is a fatal asbestos-associated malignancy originating from the lining cells (mesothelium) of the pleural and peritoneal cavities, as well as the pericardium and the tunica vaginalis. The exact prevalence is unknown but it is estimated that mesotheliomas represent less than 1% of all cancers. Its incidence is increasing, with an expected peak in the next 10-20 years. Pleural malignant mesothelioma is the most common form of mesothelioma. Typical presenting features are those of chest pain and dyspnoea. Breathlessness due to a pleural effusion without chest pain is reported in about 30% of patients. A chest wall mass, weight loss, sweating, abdominal pain and ascites (due to peritoneal involvement) are less common presentations. Mesothelioma is directly attributable to occupational asbestos exposure with a history of exposure in over 90% of cases. There is also evidence that mesothelioma may result from both para-occupational exposure and non-occupational "environmental" exposure. Idiopathic or spontaneous mesothelioma can also occur in the absence of any exposure to asbestos, with a spontaneous rate in humans of around one per million. A combination of accurate exposure history, along with examination radiology and pathology are essential to make the diagnosis. Distinguishing malignant from benign pleural disease can be challenging. The most helpful CT findings suggesting malignant pleural disease are 1) a circumferential pleural rind, 2) nodular pleural thickening, 3) pleural thickening of > 1 cm and 4) mediastinal pleural involvement. Involvement of a multidisciplinary team is recommended to ensure prompt and appropriate management, using a framework of radiotherapy, chemotherapy, surgery and symptom palliation with end of life care. Compensation issues must also be considered. Life expectancy in malignant mesothelioma is poor, with a median survival of about one year following diagnosis.
Topics: Humans; Mesothelioma; Pleural Neoplasms; Tomography, X-Ray Computed
PubMed: 19099560
DOI: 10.1186/1750-1172-3-34 -
ESMO Open Mar 2020Malignant pleural mesothelioma is a rare and aggressive malignancy mostly associated with occupational asbestos exposure. Prognosis is poor and only highly selected... (Review)
Review
Malignant pleural mesothelioma is a rare and aggressive malignancy mostly associated with occupational asbestos exposure. Prognosis is poor and only highly selected patients may benefit from aggressive surgical management, also as part of a multimodal approach. In advanced disease, the combination of pemetrexed and platinum remains the only established treatment, while efficacy evidence of second line chemotherapy is lacking. Thus, a deeper knowledge of biology of the disease and more effective treatments are urgently needed. Refer to specialised centres with multidisciplinary expertise is mandatory, as well as inclusion of patients in clinical trials is advisable whenever possible. In all stages of disease focus on symptoms control is paramount.
Topics: Humans; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Pleural Neoplasms
PubMed: 32156681
DOI: 10.1136/esmoopen-2019-000669 -
Journal of Cellular Physiology Jan 2012Malignant mesothelioma (MM) is a neoplasm arising from mesothelial cells lining the pleural, peritoneal, and pericardial cavities. Over 20 million people in the US are... (Review)
Review
Malignant mesothelioma (MM) is a neoplasm arising from mesothelial cells lining the pleural, peritoneal, and pericardial cavities. Over 20 million people in the US are at risk of developing MM due to asbestos exposure. MM mortality rates are estimated to increase by 5-10% per year in most industrialized countries until about 2020. The incidence of MM in men has continued to rise during the past 50 years, while the incidence in women appears largely unchanged. It is estimated that about 50-80% of pleural MM in men and 20-30% in women developed in individuals whose history indicates asbestos exposure(s) above that expected from most background settings. While rare for women, about 30% of peritoneal mesothelioma in men has been associated with exposure to asbestos. Erionite is a potent carcinogenic mineral fiber capable of causing both pleural and peritoneal MM. Since erionite is considerably less widespread than asbestos, the number of MM cases associated with erionite exposure is smaller. Asbestos induces DNA alterations mostly by inducing mesothelial cells and reactive macrophages to secrete mutagenic oxygen and nitrogen species. In addition, asbestos carcinogenesis is linked to the chronic inflammatory process caused by the deposition of a sufficient number of asbestos fibers and the consequent release of pro-inflammatory molecules, especially HMGB-1, the master switch that starts the inflammatory process, and TNF-alpha by macrophages and mesothelial cells. Genetic predisposition, radiation exposure and viral infection are co-factors that can alone or together with asbestos and erionite cause MM. J. Cell. Physiol. 227: 44-58, 2012. © 2011 Wiley Periodicals, Inc.
Topics: Humans; Mesothelioma
PubMed: 21412769
DOI: 10.1002/jcp.22724 -
Archives of Pathology & Laboratory... Aug 2012Diffuse malignant mesothelioma (DMM) is an uncommon cancer with great clinical significance because it currently remains an incurable disease, and most patients die... (Review)
Review
Diffuse malignant mesothelioma (DMM) is an uncommon cancer with great clinical significance because it currently remains an incurable disease, and most patients die within months after diagnosis. Although DMM incidence is leveling off or decreasing in developed countries because of the strict control of asbestos use, it is increasing in countries without adequate asbestos control. In some settings, benign, reactive mesothelial hyperplasias and organizing pleuritis can be difficult to differentiate from DMM and vice versa, and the variety of DMM's histopathologic features generates an extensive list of differential diagnoses with other malignancies, particularly, metastatic malignancies, which are more frequent in the pleura than are primary malignancies. These two issues are the topic of discussion in this review, along with a brief presentation of a case of DMM that presented in a 66-year-old man with recurrent, right pleural effusions, and in whom, diagnosis of DMM had not been suspected clinically, radiographically, surgically, grossly, or initially, on frozen section. It was not until focal invasion into the skeletal muscle was discovered on permanent sections that a diagnosis of DMM could be established.
Topics: Aged; Diagnosis, Differential; Humans; Lung; Lung Neoplasms; Male; Mesothelioma; Muscle Neoplasms; Muscle, Skeletal; Pleural Effusion, Malignant; Pleurisy
PubMed: 22849735
DOI: 10.5858/arpa.2012-0142-CR -
British Journal of Cancer Oct 2021Mesothelioma is an aggressive cancer that is associated with exposure to asbestos. Although asbestos is banned in several countries, including the UK, an epidemic of... (Review)
Review
Mesothelioma is an aggressive cancer that is associated with exposure to asbestos. Although asbestos is banned in several countries, including the UK, an epidemic of mesothelioma is predicted to affect middle-income countries during this century owing to their heavy consumption of asbestos. The prognosis for patients with mesothelioma is poor, reflecting a failure of conventional chemotherapy that has ultimately resulted from an inadequate understanding of its biology. However, recent work has revolutionised the study of mesothelioma, identifying genetic and pathophysiological vulnerabilities, including the loss of tumour suppressors, epigenetic dysregulation and susceptibility to nutrient stress. We discuss how this knowledge, combined with advances in immunotherapy, is enabling the development of novel targeted therapies.
Topics: Asbestos; Combined Modality Therapy; Epigenesis, Genetic; Gene Regulatory Networks; Humans; Mesothelioma; Prognosis
PubMed: 34226685
DOI: 10.1038/s41416-021-01462-2 -
Archives of Pathology & Laboratory... Oct 2012The separation of benign from malignant mesothelial proliferations is crucial to patient management but is often a difficult problem for the pathologist. (Review)
Review
CONTEXT
The separation of benign from malignant mesothelial proliferations is crucial to patient management but is often a difficult problem for the pathologist.
OBJECTIVE
To review the pathologic features that allow separation of benign from malignant mesothelioma proliferations, with an emphasis on new findings.
DATA SOURCES
Literature review and experience of the authors.
CONCLUSIONS
Invasion is still the most reliable indicator of malignancy. The distribution and amount of proliferating mesothelial cells are important in separating benignity from malignancy, and keratin stains can be valuable because they highlight the distribution of mesothelial cells. Hematoxylin-eosin examination remains the gold standard, and the role of immunochemistry is extremely controversial; we believe that at present there is no reliable immunohistochemical marker of malignancy in this setting. Mesothelioma in situ is a diagnosis that currently cannot be accurately made by any type of histologic examination. Desmoplastic mesotheliomas are characterized by downward growth of keratin-positive spindled cells between S100-positive fat cells; some cases of organizing pleuritis can mimic involvement of fat, but these fat-like spaces are really S100-negative artifacts aligned parallel to the pleural surface. Fluorescence in situ hybridization on tissue sections to look for homozygous p16 gene deletions is occasionally useful, but many mesotheliomas do not show homozygous p16 deletions. Equivocal biopsy specimens should be diagnosed as atypical mesothelial hyperplasia and another biopsy requested if the clinicians believe the process is malignant.
Topics: Cell Proliferation; Humans; Mesothelioma; Pleural Neoplasms
PubMed: 23020727
DOI: 10.5858/arpa.2012-0112-RA -
British Journal of Cancer Jan 2020Malignant pleural mesothelioma (MPM) is a rare malignancy of mesothelial cells with increasing incidence, and in many cases, dismal prognosis due to its aggressiveness... (Review)
Review
Malignant pleural mesothelioma (MPM) is a rare malignancy of mesothelial cells with increasing incidence, and in many cases, dismal prognosis due to its aggressiveness and lack of effective therapies. Environmental and occupational exposure to asbestos is considered the main aetiological factor for MPM. Inhaled asbestos fibres accumulate in the lungs and induce the generation of reactive oxygen species (ROS) due to the presence of iron associated with the fibrous silicates and to the activation of macrophages and inflammation. Chronic inflammation and a ROS-enriched microenvironment can foster the malignant transformation of mesothelial cells. In addition, MPM cells have a highly glycolytic metabolic profile and are positive in F-FDG PET analysis. Loss-of-function mutations of BRCA-associated protein 1 (BAP1) are a major contributor to the metabolic rewiring of MPM cells. A subset of MPM tumours show loss of the methyladenosine phosphorylase (MTAP) locus, resulting in profound alterations in polyamine metabolism, ATP and methionine salvage pathways, as well as changes in epigenetic control of gene expression. This review provides an overview of the perturbations in metabolism and ROS homoeostasis of MPM cells and the role of these alterations in malignant transformation and tumour progression.
Topics: Animals; Antineoplastic Agents; Asbestos; Cell Transformation, Neoplastic; Cisplatin; Humans; Loss of Function Mutation; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Oxidation-Reduction; Pleural Neoplasms; Reactive Oxygen Species; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Suppressor Proteins; Ubiquitin Thiolesterase
PubMed: 31819191
DOI: 10.1038/s41416-019-0661-9