Tumour Review
The established and future biomarkers of malignant pleural mesothelioma

https://doi.org/10.1016/j.ctrv.2015.05.001Get rights and content

Highlights

  • A review of front line diagnostic, prognostic, predictive mesothelioma biomarkers.

  • Circulating mesothelin and pleural fluid hyaluronate/N-ERC mesothelin, may be helpful adjuvant diagnostic tools.

  • Non-coding RNAs, proteomics and hyaluronan may be important future markers.

  • Tumor gene-ratio, FISH assay and deformability cytometry emerge as promising tests.

  • Mutations of the BAP1 gene are novel susceptibility markers for mesothelioma.

Abstract

Malignant pleural mesothelioma (MPM) is an asbestos-related cancer with a median survival of 12 months. The MPM incidence is 1–6/100,000 and is increasing as a result of historic asbestos exposure in industrialized countries and continued use of asbestos in developing countries. Lack of accurate biomarkers makes diagnosis, prognostication and treatment prediction of MPM challenging. The aim of this review is to identify the front line of MPM biomarkers with current or potential clinical impact. Literature search using the PubMed and PLoS One databases, the related-articles function of PubMed and the reference lists of associated publications until April 26th 2015 revealed a plethora of candidate biomarkers. The current gold standard of MPM diagnosis is a combination of two positive and two negative immunohistochemical markers in the epithelioid and biphasic type, but sarcomatous type do not have specific markers, making diagnosis more difficult. Mesothelin in serum and pleural fluid may serve as adjuvant diagnostic with high specificity but low sensitivity. Circulating proteomic and microRNA signatures, fibulin-3, tumor cell gene-ratio test, transcriptomic, lncRNA, glycopeptides, pleural fluid FISH assay, hyaluronate/N-ERC mesothelin and deformability cytometry may be important future markers. Putative predictive markers for pemetrexed–platinum are tumor TS and TYMS, for vinorelbine the ERCC1, beta-tubuline class III and BRCA1. Mutations of the BAP1 gene are potential markers of MPM susceptibility. In conclusion, the current status of MPM biomarkers is not satisfactory but encouraging as more sensitive and specific non-invasive markers are emerging. However, prospective validation is needed before clinical application.

Introduction

Malignant mesothelioma (MM) is a highly lethal tumor of the pleura and peritoneum (common ratio 4:1) and rarely pericardium and tunica vaginalis testis [1], [2]. Inhalation of asbestos is the carcinogenic factor in more than 80% of cases [3], but exposure to erionite, alpha-emitting contrast medium or irradiation of the thorax or abdomen in young age are also verified risk factors [1]. Initially, only occupational asbestos exposure was considered dangerous, but subsequent research has shown that environmental exposure by sharing residence with an asbestos worker and even living near an asbestos-emitting location increases risk considerably [1], [3].

The diagnosis of malignant pleural mesothelioma (MPM) can be challenging due to similarities in clinical presentation and histological appearance of MPM, primary lung carcinoma, pleural metastases, reactive pleural diseases and rare pleural malignancies [4]. International pathological classification distinguishes three histopathological subtypes; epithelioid, sarcomatous, and biphasic MPM. The epithelioid and biphasic subtypes, which comprise 75–95% of all cases, have a relatively well-characterized immunophenotype [4]. On the other hand, relatively few studies of sarcomatous MPM have been reported and the histopathological diagnosis of sarcomatous MPM is still challenging [4], [5].

MPM is a relatively chemo- and radio-resistant malignancy, and patients treated with pemetrexed–cisplatin have a median survival of 12.1 months, but occasionally long-term survivors are seen [6]. Radiation monotherapy has been disappointing, but encouraging results were shown with postoperative Intensity Modulated Radiation Therapy (IMRT) [7]. However, the only study were patients were randomized to trimodal treatment of chemotherapy, extra-pleural pneumonectomy (EPP) and radiotherapy by IMRT versus chemotherapy alone (MARS study), did not show any difference in survival [8]. The MARS study had, though, considerable limitations, as 44.6% of the patients did not proceed to randomization because of disease progression, patient choice or inoperability. Furthermore, only 66.7% of the patients randomized to EPP completed surgery, and 23.1% of the non-EPP patients decided to have EPP or other surgery off trial. Currently, radical pleurectomy/decortication of pleura has been proposed as a less traumatic procedure with decreased morbidity and encouraging data showed that combined with chemotherapy and high-dose radiation therapy the overall survival was 33 months in a small cohort [9], [10]. Symptomatic treatment of recurrent pleural fluid with talc pleurodesis decreasing pleural fluid, improve respiration, and has even shown to increase survival in small series [11]. Psychological backing of patient and family and good palliative care is of utmost importance.

Early diagnosis of MPM could increase the overall survival, but pre-clinical biomarkers are not yet available [12]. Prognosis is positively correlated with epithelioid subtype, low stage, performance status, female gender and young age, but biomarkers of response and outcome are still not in clinical use [13]. The aim of this review is to present the current and the most promising future MPM biomarkers.

Section snippets

Methods

The PubMed and PLoS One databases and the reference lists of associated publications were used in this literature search with the following keywords: “malignant mesothelioma” combined with “biomarkers”, “immunohistochemistry”, “BAP-1”, “deformability cytometry”, “fibulin-3”, “genome profile”, “hyaluronan”, “long non-coding RNA”, “mesothelin”, “microRNA”, “osteopontin”, “proteomics” and “soluble mesothelin related protein”. No lower data limit was applied and only articles written in English

Results and discussion

The search revealed a plethora of MPM biomarkers described with varying specificity and sensitivity. Markers in tumor and in body fluids with a current or promising clinical impact are discussed in this review.

Conclusion

Biomarkers have been studied in relation to the diagnosis and prognosis of MPM with varying specificity and sensitivity in many contradicting studies. The current gold standard of MPM diagnosis is a combination of two positive and two negative immunohistochemical markers in tumor, while the sarcomatoid type still is a diagnostic challenge. Mesothelin in serum and pleural fluid may serve as adjuvant diagnostic tool with high specificity but low sensitivity. Circulating proteomic and microRNA

Conflict of interest

The authors declare that there is no conflict of interest.

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