Malignant pleural mesothelioma: an update

Abstract

Malignant mesotheliomas are rare types of cancers that affect the mesothelial surfaces, usually the pleura and peritoneum. They are associated with asbestos exposure, but due to a latency period of more than 30 years and difficult diagnosis, most cases are not detected until they reach advanced stages. Treatment options for this tumor type are very limited and survival ranges from 12 to 36 months. This review discusses the molecular physiopathology, current diagnosis, and latest therapeutic options for this disease.

Figure 1. Molecular mechanisms associated with MM pathogenesis. Inhaled asbestos fibers transverse terminal airways and lodge themselves in the pleural space. Macrophages try to phagocytize these fibers without effect and in doing that they release reactive oxygen species and reactive nitrogen species, which may promote genotoxic damage, and recruit other inflammatory and immune cells. Repeated DNA damage by ROS and RNS may lead to the accumulation of oncogenic mutations in the mesothelial cells. The genes most frequently mutated in mesothelioma and that may be associated with malignant transformation of mesothelial cells are involved with DNA repair, the Hippo pathway, cell cycle control, DNA methylation and the mTOR pathway. Germ line mutations in genes associated with DNA repair (BAP1, BRCA1, CHECK2, etc) are found in 12% of mesothelioma patients and are associated with earlier disease onset and good prognosis. In parallel, the inflammatory mediators released in the microenvironment may promote cell survival (inhibiting apoptotic signals) and stimulate mesothelial cell proliferation (even in the presence of DNA damage), activate fibroblast to produce extracellular matrix proteins, and promote neoagiogenesis. These modifications favor tumor growth and create an immunossupressive milieu. Mø-macrophages; ROS-reactive oxygen species; RNS-reactive nitrogen species; NGF-neurotrophic growth factor; VEGF-vascular endothelial growth factor. Created with BioRender.com.

Figure 2. Representative images of the thorax from a male patient diagnosed with biphasic pleural malignant mesothelioma. (A) CT scan showing multiples areas on pleural thickening in the fissure, as well as in mediastinal and parietal pleura, sometimes forming pleural nodules, can be seen in the left hemithorax (red small arrows); (B) 18-FDG PET-CT scan showing various areas of hypermetabolic (glucose avid) tissue in the pleura can be observed on the left hemithorax.

Figure 3. Photomicrographs of MPM. (A-D) epithelioid mesothelioma. (A) H&E staining showing atypical mesothelial cells arranged in papillary and tubulo-glandular patterns amid loose connective tissue. 200x; (B) loss of BAP1 expression in the nucleus of tumor cells, DAB IHC, 200x; (C) calretinin expression in tumor cells cytoplasm, DAB IHC, 200x; (D) D2-40 expression in tumor cells membranes; (E-G) Pleomorphic/solid epithelioid MPM; (E) H&E staining, 100x; (F) BAP1 expression in the nucleus of tumor cells, DAB IHC, 200x; (G) calretinin expression in tumor cells cytoplasm; (H-J) Papillary MPM. H) H&E staining showing a monolayer of mesothelial cells with low grade nuclear atypia covering a fibrovascular core, 100x; (I) calretinin expression in the nucleus and cytoplasm of tumor cells, DAB IHC, 100x; (J) WT1 expression in the nucleus of tumor cells, DAB IHC, 200x; (K-L) Desmoplastic MPM; (K) H&E staining showing isolated round and spindled mesothelial cells amidst a dense desmoplastic stroma, 40x; (L) WT1 expression in the nucleus of tumor cells., DAB IHC, 200x. DAB- 3,3’-diamino-benzidine. H&E- hematoxylin and eosin. IHC-immunohistochemistry.

Figure 4. Diagram summarizing current treatment for MPM. It should be highlighted that, if available, all patients must be considered for participation in investigational clinical trials.DP: disease progression.