Molecular markers and new diagnostic methods to differentiate malignant from benign mesothelial pleural proliferations: a literature review

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive tumor associated with asbestos exposure. Histopathological analysis of pleural tissues is the gold standard for diagnosis; however, it can be difficult to differentiate malignant from benign pleural lesions. The purpose of this review is to describe the most important biomarkers and new diagnostic tools suggested for this differential diagnosis. There are many studies concerning the separation between MPM and benign pleural proliferations from both pleural tissues or effusions; most of them are based on the evaluation of one or few biomarkers by immunohistochemistry (IHC) or enzyme-linked immunosorbent assays (ELISAs), whereas others focused on the identification of MPM signatures given by microRNA (miRNA) or gene expression profiles as well as on the combination of molecular data and classification algorithms. None of the reported biomarkers showed adequate diagnostic accuracy, except for p16 [evaluated by fluorescent in situ hybridization (FISH)] and BAP1 (evaluated by IHC), both biomarkers are recommended by the International Mesothelioma Interest Group guidelines for histological and cytological diagnosis. BAP1 and p16 showed a specificity of 100% in discerning malignant from benign lesions because they are exclusively unexpressed or deleted in MPM. However, their sensitivity, even when used together, is not completely sufficient, and absence of their alterations cannot confirm the benign nature of the lesion. Recently, the availability of new techniques and increasing knowledge regarding MPM genetics led to the definition of some molecular panels, including genes or miRNAs specifically deregulated in MPM, that are extremely valuable for differential diagnosis. Moreover, the development of classification algorithms is facilitating the application of molecular data for clinical practice. Data regarding new diagnostic tools and MPM signatures are absolutely promising; however, before their application in clinical practice, a prospective validation is necessary, as these approaches could surely improve the differential diagnosis between malignant and benign pleural lesions.

Guidelines for the cytopathologic diagnosis of epithelioid and mixed‐type malignant mesothelioma: Complementary statement from the international mesothelioma interest group, also endorsed by the international academy of cytology and the papanicolaou society of cytopathology. A proposal to be applauded and promoted but which requires updating

“…Whilst the only well‐founded current routinely available molecular technique for mesothelioma diagnosis is FISH for p16 deletion (and this is referred to briefly in the guideline), there are many other techniques that are evolving and which may become more widely available in the future. These include microRNA expression and DNA methylation in tissue or in circulating tumour cells/circulating tumour DNA . Any update of the guidelines will need to introduce these and discuss any potential role they may have now, or promise they might have for the future.…”

Signaling pathways associated with interleukins 12 and 23 and epigenetic mechanism of sequential-specific regulation of expression of related genes by miRNAs as molecular markers for assessing the potential of anti-cytokine therapies

“…Given the above, seeking new molecular markers that would allow for determining treatment efficacy and notice the lack of adequate response to the applied therapeutic strategy at an early stage, regardless of the therapy or drug type, is of the essence [4,5,13].…”

“…Z tego względu niezwykle istotne jest poszukiwanie nowych molekularnych markerów, które niezależnie od rodzaju terapii i wyboru leku pozwoliłyby określić efektywność leczenia oraz na wczesnym etapie wychwycić brak adekwatnej odpowiedzi na stosowaną strategię terapeutyczną [4,5,13].…”

A gene‑expression‑based test can outperform bap1 and p16 analyses in the differential diagnosis of pleural mesothelial proliferations

“…A variety of ancillary tests, mostly based on the evaluation of immunohistochemical markers, have been claimed to be useful for separating benign from malignant mesothelial proliferations either on pleural tissues or effusions (7). However, the majority of these markers did not achieve sufficient diagnostic accuracy.…”