Authored by Attapon Cheepsattayakorn*
Abstract
The objectives of this study are to review epidemiology, novel methods of detection, and novel diagnostics of malignant pleural mesothelioma (MPM) in the literature that were published between 1977 and 2019. Malignant pleural mesothelioma associated with prolonged respirable-asbestosfiber exposure is a rare cancer with constantly increasing incidence and poor prognosis due to lacking the effective treatment options. The median survival ranges from 8 to 14 months. Sarcomatoid histological subtype has the worst prognosis. Video-assisted thoracoscopy plus mediastinoscopy is the current gold standard for staging malignant pleural mesothelioma and is superior to computerized tomography of the chest for assessing the tumor size and suspected nodal metastases. Several circulating biomarkers are detected in MPM patients, such as mesothelin, osteopontin, fibulin-3, high mobility group B1, vascular endothelial growth factor, reactive oxygen species, reactive nitrogen species, micro-ribonucleic acids, tumor deoxyribonucleic acid, etc. In conclusion, there is potential for the development of biomarkers and radiological imaging in the years to come. Its incidence is expected to decrease in the next decade.
Keywords: Pleural; Mesothelioma; Malignant; Diagnosis; Epidemiology
Abbreviations: BALF : Bronchoalveolar lavage; BAP1 : BRCA-associated protein 1; CFAP45 : Cilia and flagella associated protein 45; CT : Computed tomography; CTCs : Circulating tumor cells; ctDNA : circulating tumor Deoxyribonucleic acid; DNA : Deoxyribonucleic acid; FDG : 18-fluoro-deoxyglucose; HMGB1 : High Mobility Group B1 ; miRNAs : micro-Ribonucleic acids; MPM : Malignant pleural mesothelioma; MRI : Magnetic resonance imaging ; MSLN : Mesothelin; PDGF : Platelet-derived growth factor; PET-CT : Positron-emission technology-computed tomography; RNS : Reactive nitrogen species; ROS : Reactive oxygen species; RR2 : Ryanodine receptor 2; SETDB1 : Set domain bifurcated 1; SETD2 : Set domain containing 2; SMRP : Soluble mesothelin-related peptide; TGF-β : Tumor growth factor-β ; TNM : Tumor-nodes-metastases; UICC : the Union for International Cancer Control ; UK : United Kingdom; ULK2 : Unc-like autophagy activating kinase; USA : United States of America; US FDA : United States Food and Drug Administration; VATS : Video-assisted thoracoscopic surgery; VEGF : Vascular endothelial growth factor
Objectives of the Study
The objectives of this study are to review epidemiology, novel methods of detection, and novel diagnostics of malignant pleural mesothelioma (MPM) in the literature that were published between 1977 and 2019.
Introduction
Malignant pleural mesothelioma, a tumor originated from the submesothelial or mesothelial cells of pleura, pericardium, or peritoneum accounts for more than 80 % arising from the pleura that the majority are male patients [1,2]. MPM, a rare cancer with increasing incidence and poor prognosis because of lacking the effective therapeutic interventions [1,3-4]. MPM is associated with previous long-term asbestos exposure of about 40 years of latency period [5-9]. The total incidence is highest in the UK and USA whereas the global incidence has increased constantly over the past decade and is predicted to reach the estimated peak in 2020 [5,6]. The median survival of MPM ranges from 8 to 14 months from the diagnosis [5-7,10]. Male is predominant of 4 : 1 [10]. Four main histological subtypes of MPM are classified as the following : 1) epithelioid ( most favorable prognosis with a median survival of 13.1 months), 2) sarcomatoid (worst outcomes with a median survival of 4 months), 3) biphasic or mixed, and 4) desmoplastic [5, 6,10].
Pathogenesis
Prolonged exposure to respirable asbestos fibers triggers an increase in inflammatory cytokines and reactive oxygen species (ROS) in the pleural microenvironment, both of which facilitate MPM carcinogenesis [11,12]. Naturally, asbestos occurs in the form of silicate mineral with two different forms : 1) curly serpentine fibers of chrysotile or “ white ” asbestos and 2) sharp, needle-like fibers of amphibole asbestos. Amphibole asbestos is divided into 2.1) crocidolite (blue) asbestos, 2.2) amosite (brown) asbestos, 2.3) anthophyllite, 2.4) actinolite, and 2.5) tremolite. The risk of MPM development is associate with the type of fibers and heaviness and duration of exposure [5]. Nevertheless, MPM is characterized by a low mutation load [13], with the most frequently mutated genes involved in MPM pathogenesis, “ tumor suppressors (BAP1, CDKN2A, LATS2, NF2) [14]. After asbestos fibers are inhaled and migrate to the pleural space causing pleural irritation and a repeated cycle of tissue damage and repair. Asbestos fibers that penetrate mesothelial cells that cause cell mitosis interference, generating DNA mutation, and altering chromosome structure. These mesothelial cells release inflammatory cytokines, such as plateletderived growth factor (PDGF), tumor growth factor-β (TGF-β), and vascular endothelial growth factor (VEGF) that facilitate tumor growth [9]. Asbestos fibers also induce the phosphorylation various protein kinases (extracellular signal-regulated kinase 1 and 2 and mitogen-activated protein) that increases the expression of protooncogenes and facilitating abnormal cellular proliferation [15]. In PMP tumor, there is reduced expression of key molecules in the p53 tumor-suppressor gene pathway (p14, p16, and NF2-MERLIN) [15]. There are deletions and loss mutations of BAP1 (BRCAassociated protein 1), CFAP45 (cilia and flagella associated protein 45), DDX3X, DDX51, RR2 (ryanodine receptor 2), SETDB1 (set domain bifurcated 1), SETD2 (set domain containing 2), and ULK2 (unc-like autophagy activating kinase) [16]. Nevertheless, MPM has a low frequency of protein-altering mutations, approximately 25 mutations per tumor [17] and contributing to the limitations of the potential for molecular targeted therapy [18].
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