Hyaluronan and N-ERC/mesothelin as key biomarkers in a specific two-step model to predict pleural malignant mesothelioma

Our plain-English summary of Hyaluronan and N-ERC/mesothelin as key biomarkers in a specific two-step model to predict pleural malignant mesothelioma, by F. Mundt, G. Nilsonne, S. Arslan, et al (PloS One, 2013).

The study

• Authors: F. Mundt, G. Nilsonne, S. Arslan, K. Csürös, G. Hillerdal, H. Yildirim, M. Metintas, K. Dobra, A. Hjerpe
• Journal: PloS One
• Published: 2013;8(8):e72030
• Cited by: 34 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Purpose: Diagnosis 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 Methods: Effusions 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.

Results: Biochemical 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.

Conclusions: A 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.

In plain English

This study tested whether substances measured in fluid that collects around the lungs (pleural effusions) could help diagnose malignant pleural mesothelioma. The authors measured seven markers in effusions from 190 patients at Karolinska University Hospital in Sweden: 46 with mesothelioma, 49 with other cancers and 95 with benign conditions. They then tested the resulting model on 375 effusions from a second referral centre in Eskisehir, Turkey. Hyaluronan, N-ERC/mesothelin, C-ERC/mesothelin and syndecan-1 were significantly associated with mesothelioma. Syndecan-2, osteopontin and thioredoxin were not. A two-step model using hyaluronan and N-ERC/mesothelin had an area under the ROC curve of 0.99 (95% confidence interval 0.97 to 1.00) in the Swedish data and 0.83 (0.74 to 0.91) in the Turkish data. In the Turkish data, the model detected 52.0% of mesotheliomas while correctly ruling out 98.7% of non-mesothelioma cases. At that same level, hyaluronan alone detected 16.0% and N-ERC/mesothelin alone 44.0%. The authors concluded that the model predicts mesothelioma with high specificity. They noted that diagnoses in the Turkish set were less rigorously confirmed and that tumour stage was mostly unknown.

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: Diagnostic biomarker study: a prediction model was built on one prospectively and consecutively collected set of pleural effusions and externally validated on a second set from a different centre
• Who was studied: Model generation: pleural effusions from 190 patients at Karolinska University Hospital, Huddinge, Sweden, collected 2005 to 2009 (46 mesothelioma, 49 other cancers, 95 benign). Validation: 375 effusions from the Department of Chest Diseases, Eskisehir Osmangazi University, Turkey, stored 2004 to 2009 (48 mesothelioma, 166 other cancers, 161 benign).
• Exposure: Asbestos exposure was not measured. The study measured seven biomarkers in effusion fluid: hyaluronan, N-ERC/mesothelin, C-ERC/mesothelin, osteopontin, syndecan-1, syndecan-2 and thioredoxin. The authors attributed the high proportion of women among the Turkish mesothelioma patients most likely to environmental asbestos and erionite exposure.
• Main results:
  • In the Swedish model generation dataset, these markers were significantly associated with mesothelioma, with odds ratios (95% CI): hyaluronan 8.82 (4.82 to 20.39), N-ERC/mesothelin 4.81 (3.19 to 7.93), C-ERC/mesothelin 3.58 (2.43 to 5.59), and syndecan-1 1.34 (1.03 to 1.77).
  • Syndecan-2, osteopontin and thioredoxin were not significantly associated with mesothelioma in the model generation dataset.
  • In the model generation dataset, at 100% specificity, sensitivity was 45.7% for hyaluronan, 37.9% for N-ERC/mesothelin and 87.0% for the two-step model.
  • The area under the ROC curve for the two-step model was 0.99 (95% CI 0.97 to 1.00) in the model generation dataset and 0.83 (0.74 to 0.91) in the validation dataset.
  • In the Turkish validation dataset, the two-step model had a sensitivity of 52.0% and a specificity of 98.7% at a predicted risk above 0.81.
  • In the validation dataset, at the same 98.7% specificity, sensitivity was 16.0% for hyaluronan alone and 44.0% for N-ERC/mesothelin alone.
  • In the validation dataset, five cases with a high predicted risk had other diagnoses: three metastatic cancer and two benign. Tissue was available for two of the cases diagnosed as carcinoma, and extended immunohistochemistry indicated both were mesothelioma.
• The authors' conclusion: The authors concluded that a two-step model using hyaluronan and N-ERC/mesothelin predicts mesothelioma with high specificity, can be performed on the first available effusion, and could be a useful adjunct to the morphological diagnosis of mesothelioma.
• Limitations the authors state:
  • The diagnostic reference standard in the validation dataset was less stringent: mesotheliomas had more limited immunohistochemical support, benign diagnoses were mainly clinical, and some cases lacked long-term follow-up.
  • Hyaluronan had been used in some cases to aid diagnosis in the model generation dataset, although all diagnoses were established by independent methods.
  • Information on tumour stage and grade was missing for most cases.
  • The model discriminated less well in the validation dataset, possibly partly because of model shrinkage.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelin, Biomarker, Mesothelioma, Pleural Effusion, Osteopontin, Odds Ratio.

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• Evaluation of soluble mesothelin-related peptide as a diagnostic marker of malignant pleural mesothelioma effusions: its contribution to cytology — P.A. Canessa, M.C. Franceschini, et al. (2013)
• CD44 and its ligand hyaluronan as potential biomarkers in malignant pleural mesothelioma: evidence and perspectives — L. Cortes-Dericks, R.A. Schmid (2017)
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