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

Our plain-English summary of Molecular markers and new diagnostic methods to differentiate malignant from benign mesothelial pleural proliferations: a literature review, by R. Bruno, G. Alì, G. Fontanini (Journal of Thoracic Disease, 2018).

The study

• Authors: R. Bruno, G. Alì, G. Fontanini
• Journal: Journal of Thoracic Disease
• Published: 2018;10(Suppl 2):S342-S352
• Type of article: Review
• Cited by: 21 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This article was a literature review, not a new study. The authors searched PubMed for English-language publications from the previous 10 years on telling malignant pleural mesothelioma apart from benign pleural conditions, such as reactive mesothelial hyperplasia. They left out blood serum and plasma markers used to screen asbestos-exposed people. The review covered tissue stains, markers measured in pleural fluid, microRNAs, and newer methods that combine multi-gene tests with computer classification. The authors wrote that none of the tissue-stain or pleural-fluid markers was highly sensitive. Two markers, BAP1 and p16, had never been reported as altered in benign lesions, giving 100% specificity. Their reported sensitivity ranged from 43 to 93 percent for p16 and 61 to 67 percent for BAP1, so finding no alteration could not confirm a lesion was benign. The authors described microRNA and gene-panel methods, including their own group's earlier work, as promising. They noted that all the reviewed studies were retrospective and small, with few sarcomatoid cases. They concluded that prospective validation in larger groups is needed.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Literature review of published studies on biomarkers and diagnostic methods for separating malignant pleural mesothelioma from benign pleural proliferations
• Who was studied: English-language publications found on PubMed from the previous 10 years on the pathological differential diagnosis of malignant versus benign pleural lesions. Serum and plasma biomarkers used in screening asbestos-exposed people were excluded.
• Exposure: Not an exposure study. The review concerns diagnostic markers. It describes malignant pleural mesothelioma as mainly caused by asbestos exposure, and it excluded blood-based markers used in screening asbestos-exposed people.
• Main results:
  • Across the reviewed studies, the authors found that none of the tissue (immunohistochemistry) or pleural-fluid soluble markers was highly sensitive for separating benign from malignant pleural lesions.
  • In the reviewed studies, p16 (tested by FISH) and BAP1 (tested by immunohistochemistry) had 100% specificity for malignant pleural mesothelioma. Reported sensitivity was 43 to 93% for p16 and 61 to 67% for BAP1.
  • Because BAP1 and p16 are altered in only a proportion of mesotheliomas, the review states that finding no alteration does not establish that a lesion is benign.
  • For mesothelin measured in pleural effusions, the review reports low sensitivity (60 to 70%) for diagnosing malignant pleural mesothelioma.
  • Based on the studies it reviewed, the review states that fibulin-3 measured in pleural effusions does not appear useful for diagnosing malignant pleural mesothelioma.
  • One reviewed study (Andersen et al.) reported a four-microRNA classifier that distinguished malignant pleural mesothelioma from reactive pleural proliferations with 95% sensitivity, 93% specificity and 94% overall accuracy.
  • In the authors' own group's earlier NanoString study of 117 genes, the classification models correctly assigned all 14 blindly analyzed test tissues (9 epithelioid malignant pleural mesothelioma and 5 mesothelial hyperplasia).
• The authors' conclusion: The authors concluded that microRNA signatures and new diagnostic tools are promising, but none can be used in clinical practice without proper validation. They called for prospective validation in larger cohorts.
• Limitations the authors state:
  • All studies included in the review were retrospective and based on small numbers of selected benign and malignant mesothelial proliferations.
  • The sarcomatoid type of mesothelioma was scarcely represented in the reviewed studies.
  • There are no universally accepted cut-off values for the markers reviewed.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Asbestos Exposure, Biomarker, Differential Diagnosis, Immunohistochemistry, Fluorescence In Situ Hybridization (FISH), BAP1, Mesothelioma.

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