A prospective trial evaluating the role of mesothelin in undiagnosed pleural effusions

Our plain-English summary of A prospective trial evaluating the role of mesothelin in undiagnosed pleural effusions, by C.E. Hooper, A.J. Morley, P. Virgo, et al (The European Respiratory Journal, 2013).

The study

• Authors: C.E. Hooper, A.J. Morley, P. Virgo, J.E. Harvey, B. Kahan, N.A. Maskell
• Journal: The European Respiratory Journal
• Published: 2013;41(1):18-24
• Cited by: 18 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Mesothelin has been proposed as a useful tool in the diagnosis of malignant pleural mesothelioma (MPM). We aimed to examine its diagnostic utility and the impact of renal impairment on results. We prospectively recruited 230 patients with new undiagnosed pleural effusions, testing serum (n=216) and pleural fluid (n=206) mesothelin (by ELISA) during the initial consultation. 28 (12%) out of 230 patients had MPM. Serum mesothelin gave sensitivity 59.3%, specificity 64.7%, negative predictive value (NPV) 91.2%, positive predictive value (PPV) 20.5%, and pleural fluid sensitivity 72.0%, specificity 87.5%, NPV 95.5%, PPV 46.2% for distinguishing effusions due to MPM. In a matched comparison, diagnostic characteristics of pleural fluid mesothelin were superior to serum (p=0.0001). Serum mesothelin levels in patients without MPM were higher in patients with renal impairment (p=0.007) while pleural fluid levels were unaffected. 19 (54%) out of 35 patients with a benign pleural effusion and an estimated glomerular filtration rate ≤ 59 mL · min(-1) had a false-positive serum mesothelin result. The diagnostic accuracy of pleural fluid mesothelin is superior to that of serum and is unaffected by renal function. In patients with a low pre-test probability of mesothelioma, a negative mesothelin test could be reassuring, because of its high NPV. Routine use of mesothelin testing in undiagnosed pleural effusions at presentation appears to be unhelpful.

In plain English

This prospective study at a Bristol, UK, hospital tested mesothelin, a protein measured by a laboratory test (ELISA), for diagnosing malignant pleural mesothelioma in consecutive patients with new, unexplained fluid around the lung (pleural effusion). Of 250 who consented, 230 were included; 28 had mesothelioma. In blood serum, it was positive in 16 of 27 mesotheliomas (59.3%, 95% CI 38.8 to 77.6%), negative in 114 of 176 patients without mesothelioma (64.7%, 95% CI 57.2 to 72.0%), and 16 of 78 positives (20.5%, 95% CI 12.2 to 31.1%) were mesothelioma. In pleural fluid, the matching figures were 18 of 25 (72.0%, 95% CI 50.6 to 87.9%), 147 of 168 (87.5%, 95% CI 81.5 to 92.8%) and 18 of 39 (46.2%, 95% CI 30.1 to 62.8%). Among 182 with both samples, pleural fluid did significantly better. False positives also occurred in other cancers and benign conditions, including benign asbestos-related effusion. With reduced kidney function, serum gave false positives in 19 of 35 patients with benign effusions; pleural fluid accuracy was unaffected. The authors concluded routine testing of all undiagnosed effusions appears unhelpful.

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: Prospective diagnostic accuracy study in a consecutive series of patients, with follow-up to a final diagnosis; mesothelin results were hidden from the clinical team
• Who was studied: Patients with new undiagnosed pleural effusions at a UK teaching hospital (Bristol), July 2008 to July 2010. 276 were approached and 250 consented. 20 were removed (19 for inadequate follow-up or investigations, 1 who withdrew consent), leaving 230 included patients. Their median age was 72 years; 152 were male and 78 female. 28 had biopsy-proven malignant pleural mesothelioma (23 epithelioid, 3 sarcomatoid, 2 biphasic). 15 patients without a robust final diagnosis were excluded from the accuracy analysis, leaving 215. The serum-versus-fluid comparison used 182 patients with paired samples.
• Exposure: This was a study of a diagnostic test, not of asbestos exposure. Mesothelin was measured in serum and pleural fluid with a commercial ELISA (Mesomark). The cut-offs were 1.5 nM for serum and 20 nM for pleural fluid. 47 patients had definite and 20 had probable asbestos exposure. Fiber types were not reported.
• Main results:
  • 28 of 230 included patients had malignant pleural mesothelioma (23 epithelioid, 3 sarcomatoid, 2 biphasic).
  • Median serum mesothelin was 2.10 (interquartile range 0.80 to 6.91) nM in 27 patients with mesothelioma. This was significantly higher than 1.17 (0.90 to 1.91) nM in 176 patients with a confirmed non-mesothelioma diagnosis (p = 0.04).
  • Median pleural fluid mesothelin was 41.2 (14.7 to 70.0) nM in 25 patients with mesothelioma. This was significantly higher than 5.90 (2.85 to 11.0) nM in 168 non-mesothelioma patients (p less than 0.0001).
  • Serum mesothelin at a 1.5 nM cut-off was analysed in 27 mesothelioma and 176 non-mesothelioma patients. 16 of 27 were positive: sensitivity 59.3% (95% CI 38.8 to 77.6%). 114 of 176 were negative: specificity 64.7% (95% CI 57.2 to 72.0%). 16 of 78 positives had mesothelioma: positive predictive value 20.5% (95% CI 12.2 to 31.1%). Negative predictive value was 91.2% (95% CI 84.8 to 95.5%).
  • Pleural fluid mesothelin at a 20 nM cut-off was analysed in 25 mesothelioma and 168 non-mesothelioma patients. 18 of 25 were positive: sensitivity 72.0% (95% CI 50.6 to 87.9%). 147 of 168 were negative: specificity 87.5% (95% CI 81.5 to 92.8%). 18 of 39 positives had mesothelioma: positive predictive value 46.2% (95% CI 30.1 to 62.8%). Negative predictive value was 95.5% (95% CI 90.8 to 98.2%).
  • In 182 patients with both sample types and a confirmed diagnosis (24 with mesothelioma), the area under the curve was 0.61 (95% CI 0.46 to 0.77) for serum and 0.85 (95% CI 0.77 to 0.94) for pleural fluid. Serum was significantly inferior (p = 0.0001).
  • Among patients with malignant pleural effusions from cancers other than mesothelioma, serum mesothelin was positive in 26 (38%) of 69 and pleural fluid mesothelin in 19 (26%) of 71.
  • Among patients with benign diagnoses, 36 (34%) of 107 had a positive serum result. Pleural fluid was positive in only two benign patients, both with benign asbestos-related pleural effusion. Serum was positive in five of 13 patients with benign asbestos-related pleural effusion.
  • Serum results were falsely negative in 3 of 3 sarcomatoid, 1 of 2 biphasic and 7 of 22 epithelioid mesothelioma patients. Pleural fluid results were falsely negative in 3 of 3 sarcomatoid and 4 of 20 epithelioid cases.
  • Serum mesothelin specificity was 72.3% (95% CI 63.3 to 80.1%) in patients with eGFR above 59 mL/min. It was 49.1% (95% CI 35.6 to 62.7%) in those with eGFR of 59 mL/min or less (stage 3 chronic kidney disease or greater). In that lower-kidney-function group, 19 (54%) of 35 patients with a benign effusion had a false-positive serum result.
  • Pleural fluid mesothelin accuracy did not differ significantly between the two kidney function groups. Specificity was 86.0% with eGFR above 59 mL/min and 87.0% with eGFR of 59 mL/min or less.
• The authors' conclusion: The authors concluded that routine mesothelin testing in all undiagnosed pleural effusions is unhelpful. They said that if the test is used for diagnosis, pleural fluid should be used rather than serum, especially in patients with reduced kidney function. They said a negative result in a patient with low pre-test probability is reassuring for an absence of epithelioid mesothelioma. They said positive results should be interpreted with caution, and that the test's role in mesothelioma diagnosis appears limited.
• Limitations the authors state:
  • The proportion of patients with mesothelioma was low compared with most earlier studies, which selected samples from tissue banks. The authors say this reflects their consecutive patient population.
  • Using previously established cut-off levels may give poorer diagnostic performance than cut-offs derived for this patient population.
  • Commercially available ELISAs have not been validated for use on pleural fluid, which tempers the conclusions about pleural fluid testing.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Pleural plaques and thickening.

Medical terms in this study, explained in our Lexicon: Mesothelin, Pleural Effusion, Pleural Mesothelioma, Mesothelioma.

Related studies

• Clinical significance of pleural effusion mesothelin in malignant pleural mesothelioma — S. Yamada, C. Tabata, et al. (2011)
• Prediagnostic detection of mesothelioma by circulating calretinin and mesothelin - a case-control comparison nested into a prospective cohort of asbestos-exposed workers — G. Johnen, K. Burek, et al. (2018)
• Diagnostic value of soluble mesothelin-related peptides in pleural effusion for malignant pleural mesothelioma: An updated meta-analysis — R. Gao, F. Wang, et al. (2019)
• Is soluble mesothelin-related protein an upfront predictive marker of pleural mesothelioma? A prospective study on Italian workers exposed to asbestos — R. Filiberti, P. Marroni, et al. (2014)
• Comparison of the diagnostic accuracy of the MSLN gene products, mesothelin and megakaryocyte potentiating factor, as biomarkers for mesothelioma in pleural effusions and serum — J. Creaney, S. Sneddon, et al. (2013)
• 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)

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