The Use of Immunohistochemistry, Fluorescence in situ Hybridization, and Emerging Epigenetic Markers in the Diagnosis of Malignant Pleural Mesothelioma (MPM): A Review

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive asbestos related disease that is generally considered to be difficult to diagnose, stage and treat. The diagnostic process is continuing to evolve and requires highly skilled pathology input, and generally an extensive list of biomarkers for definitive diagnosis. Diagnosis of MPM requires histological evidence of invasion by malignant mesothelial cells often confirmed by various immunohistochemical biomarkers in order to separate it from pleural metastatic carcinoma. Often when invasion of neoplastic mesothelial cells into adjacent tissue is not apparent, further immunohistochemical testing-namely BAP1 and MTAP, as well as FISH testing for loss of p16 (CDKN2A) are used to separate reactive mesothelial proliferation due to benign processes, from MPM. Various combinations of these markers, such as BAP1 and/or MTAP immunohistochemistry alongside FISH testing for loss of p16, have shown excellent sensitivity and specificity in the diagnosis of MPM. Additionally, over the recent years, research into epigenetic marker use in the diagnosis of MPM has gained momentum. Although still in their research stages, various markers in DNA methylation, long non-coding RNA, micro RNA, circular RNA, and histone modifications have all been found to support diagnosis of MPM with generally good sensitivity and specificity. Many of these studies are however, limited by small sample sizes or other study limitations and further research into the area would be beneficial. Epigenetic markers show promise for use in the future to facilitate the diagnosis of MPM.

Mesothelioma Malignancy and the Microenvironment: Molecular Mechanisms

“…In this scenario of a low mutational burden, epigenetic regulation is considered to significantly contribute to the malignant mesothelial transformation. Particularly for cancers linked to environmental insults such as mesothelioma, the study of epigenetics has been demonstrated to be a useful indicator of disease risk, with diagnostic and prognostic value [ 26 , 27 , 28 , 29 ]. However, the deregulation of genes and protein expression described above contribute to, rather than determine, the MPM onset.…”

Liquid Biopsies from Pleural Effusions and Plasma from Patients with Malignant Pleural Mesothelioma: A Feasibility Study

“…We foresee that the use of PF or plasma could be very important in the diagnosis process and for a noninvasive clinical follow-up of the patients. An earlier diagnosis could be carried out by integrating the results of ctDNA analysis with currently available biomarkers, such as serum soluble mesothelin levels, and other epigenetic biomarkers under research, such as the expression of the circulating microRNAs miR-16, miR-17, miR-126, miR-486 or CpG methylation at CDKN2A or SFRP genes [ 23 ]. In fact, once the tumor is characterized for its genetic background, specific mutations could be used to monitor the evolution of the disease, allowing early detection of its worsening before any clinical observation.…”

Epigenetic Regulation in Exposome-Induced Tumorigenesis: Emerging Roles of ncRNAs

“…Asbestos-associated lung cancer exhibits less methylation variability than lung cancers in general, and to a substantial extent, the variability is restricted to promoter regions [102]. Additionally, asbestos exposure is highly related to malignant pleural mesothelioma (MPM) development [103], in which various markers of DNA methylation, ncRNAs, and histone modifications have been proposed as diagnostic markers involved in the progression of MPM [104]. In this sense, lncRNA-RP1 and miR-2053 were part of a four-RNA signature in serum, in combination with the DNA damage regulated autophagy modulator 1 (DRAM1) and arylsulfatase A (ARSA) exclusively in MPM patients [105].…”