Hyaluronan and N-ERC/Mesothelin as Key Biomarkers in a Specific Two-Step Model to Predict Pleural Malignant Mesothelioma

Filip Mundt,Gustav Nilsonne,Muzaffer Metintas,Gunnar Hillerdal,Sertaç Arslan,Katalin Dobra,Anders Hjerpe,Karola Csürös,Huseyin Yildirim,Konradin Metze

doi:10.1371/journal.pone.0072030

Abstract

PurposeDiagnosis of malignant mesothelioma is challenging. The first available diagnostic material is often an effusion and biochemical analysis of soluble markers may provide additional diagnostic information. This study aimed to establish a predictive model using biomarkers from pleural effusions, to allow early and accurate diagnosis.Patients and MethodsEffusions were collected prospectively from 190 consecutive patients at a regional referral centre. Hyaluronan, N-ERC/mesothelin, C-ERC/mesothelin, osteopontin, syndecan-1, syndecan-2, and thioredoxin were measured using ELISA and HPLC. A predictive model was generated and validated using a second prospective set of 375 effusions collected consecutively at a different referral centre.ResultsBiochemical markers significantly associated with mesothelioma were hyaluronan (odds ratio, 95% CI: 8.82, 4.82–20.39), N-ERC/mesothelin (4.81, 3.19–7.93), CERC/mesothelin (3.58, 2.43–5.59) and syndecan-1 (1.34, 1.03–1.77). A two-step model using hyaluronan and N-ERC/mesothelin, and combining a threshold decision rule with logistic regression, yielded good discrimination with an area under the ROC curve of 0.99 (95% CI: 0.97–1.00) in the model generation dataset and 0.83 (0.74–0.91) in the validation dataset, respectively.ConclusionsA two-step model using hyaluronan and N-ERC/mesothelin predicts mesothelioma with high specificity. This method can be performed on the first available effusion and could be a useful adjunct to the morphological diagnosis of mesothelioma.

Highlights

Malignant mesothelioma is an asbestos related cancer with a dismal prognosis, originating most commonly in the pleura or peritoneum
Biochemical markers significantly associated with mesothelioma were hyaluronan, N-ERC/mesothelin (4.81, 3.19–7.93), CERC/mesothelin (3.58, 2.43–5.59) and syndecan-1 (1.34, 1.03–1.77)
A two-step model using hyaluronan and N-ERC/mesothelin, and combining a threshold decision rule with logistic regression, yielded good discrimination with an area under the ROC curve of 0.99 in the model generation dataset and 0.83 (0.74–0.91) in the validation dataset, respectively

Summary

Introduction

Malignant mesothelioma is an asbestos related cancer with a dismal prognosis, originating most commonly in the pleura or peritoneum. In centres with access to cytologists experienced with mesothelioma diagnosis, effusion cytology in combination with immunocytochemistry, fluorescent in situ hybridization, and/or electron microscopy is sufficient for diagnosis in the majority of cases [1,2,3,4]. In those cases where these methods are not sufficient in order to reach a completely conclusive diagnosis, analyses of soluble biomarkers from effusions may be a useful complement to the morphological assessment

Objectives

Methods

Results