Pleural effusion hyaluronic acid as a prognostic marker in pleural malignant mesothelioma

Our plain-English summary of Pleural effusion hyaluronic acid as a prognostic marker in pleural malignant mesothelioma, by J. Creaney, I.M. Dick, A. Segal, et al (Lung Cancer, 2013).

The study

• Authors: J. Creaney, I.M. Dick, A. Segal, A.W. Musk, B.W. Robinson
• Journal: Lung Cancer
• Published: 2013;82(3):491-8
• Cited by: 48 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Malignant mesothelioma (MM), a primarily asbestos-induced tumour, has a poor prognosis, with over-all 5-year survival less than 5%. Tumour biomarkers are being intensely investigated in MM as aids to diagnosis and prognosis. Hyaluronic acid (HA) is produced in MM but its role in prognostication remains uncertain.

Materials And Methods: HA concentrations were determined in matching serum and pleural effusion of 96 MM patients, 26 lung cancer patients and 42 patients with benign effusions resulting from infectious, cardiac, renal, liver and rheumatoid diseases and compared to the current 'best practice' biomarker, mesothelin. Liver and kidney function were determined for each patient. Diagnostic accuracy was determined by area under the receiver operator characteristic curve (AUC) analysis following logistic regression modelling. Difference in survival between groups was determined by both log-rank test and Cox proportional hazards regression modelling.

Results: For effusion HA, the AUC (IQ range) was 0.89 (0.82-0.94) and for effusion mesothelin, it was 0.85 (0.78-0.90). Serum HA was not diagnostically useful. A combined measure of effusion HA, and serum and effusion mesothelin had an AUC of 0.92 (0.86-0.96), which was significantly higher than effusion mesothelin alone. Effusion HA had a biphasic distribution in MM patients, dichotomised at a concentration of 75 mg/L. The median survival of MM patients with high effusion HA was 18.0 (13.7-22.4) months, significantly longer than those with low HA effusion levels (12.6 months (8.4-16.8), p=0.004). Serum HA, and effusion and serum mesothelin were not significant prognostic indicators.

Conclusion: This study demonstrates that a combined biomarker panel has greater diagnostic accuracy than effusion mesothelin alone, and that significant prognostic information is provided by effusion HA.

Crown Copyright © 2013. Published by Elsevier Ireland Ltd. All rights reserved.

In plain English

This Perth, Australia study measured hyaluronic acid (HA) and mesothelin in matched serum and pleural effusion (fluid around the lung) from 96 malignant mesothelioma (MM), 26 lung cancer and 42 benign-effusion patients, 2003–2010. No asbestos-exposure assessment was reported. Median effusion HA was 62.4 in MM, 12.7 in lung cancer and 8.7 in benign patients (units conflict: mg/mL in the text, mg/L in the abstract). Serum HA did not differ significantly between groups. Separating MM from all others, effusion HA (accuracy score 0.888, 95% CI 0.824–0.935; 1.0 is perfect) and effusion mesothelin (0.847, 0.777–0.902) did not differ significantly. Combining effusion HA, effusion mesothelin and serum mesothelin scored 0.915 (0.857–0.956), significantly better than effusion mesothelin alone. MM patients with effusion HA below 75 (mg/mL in the text, mg/L in the abstract) survived a median 12.6 months (95% CI 8.4–16.8), against 18.0 months (13.7–22.4) for those above it (p = 0.004). Serum HA and serum and effusion mesothelin were not significant prognostic indicators. The authors concluded that the combined panel outperformed effusion mesothelin alone for diagnosis and that effusion HA gave significant prognostic information.

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: Biomarker study (diagnostic accuracy and survival) using stored effusion and serum samples randomly selected from a tissue bank, with patients followed in hospital records until death or censoring (median follow-up 10 months)
• Who was studied: Patients at Sir Charles Gairdner Hospital, Perth, Western Australia, who needed pleural fluid drainage between 2003 and 2010. The groups were 96 MM patients (53 epithelioid, 2 sarcomatoid, 9 biphasic, 32 histology not specified), 26 lung cancer patients and 42 patients with benign effusions from infectious, cardiac, renal, liver and rheumatoid diseases. The MM group was 86 male and 10 female.
• Exposure: No asbestos-exposure assessment was reported. The study measured hyaluronic acid (HA) and mesothelin concentrations in pleural effusion and serum, along with liver and kidney function.
• Main results:
  • Effusion HA was significantly higher in MM patients (median 62.4) than in lung cancer patients (12.7, p < 0.001) and in patients with benign effusions (8.7, p < 0.001). The body text gives these values in mg/mL, but the abstract uses mg/L for effusion HA.
  • Serum HA did not differ significantly between MM patients and patients with benign effusions or lung cancer.
  • At the 20 nM cut-off, effusion mesothelin had 60% sensitivity for MM and 91% specificity compared with the benign and lung cancer effusions.
  • In distinguishing MM from the benign and lung cancer groups combined, the AUC was 0.888 (95% CI 0.824–0.935) for effusion HA and 0.847 (0.777–0.902) for effusion mesothelin, with no significant difference between them.
  • Combining the two effusion markers significantly raised the AUC above effusion mesothelin alone. Adding serum mesothelin brought the AUC to 0.915 (95% CI 0.857–0.956) for MM compared with the benign and lung cancer groups. These probabilities were adjusted for gender.
  • MM patients with low effusion HA had a median survival of 12.6 months (95% CI 8.4–16.8). The body text sets the low-HA cut-off at below 75 mg/ml; the abstract says mg/L.
  • MM patients with high effusion HA had a median survival of 18.0 months (95% CI 13.7–22.4), significantly longer than the low-HA group (p = 0.004).
  • In a Cox regression adjusted for sex and age, the hazard ratio was 0.55 (95% CI 0.42–0.73) for each 1 log unit increase in effusion HA in MM patients.
  • In this study, effusion mesothelin, serum mesothelin, serum HA, and the effusion-to-serum ratio of either marker were not significant prognostic indicators.
• The authors' conclusion: The authors concluded that a combined biomarker panel had greater diagnostic accuracy than effusion mesothelin alone, and that effusion HA provided significant prognostic information. In MM patients, high effusion HA was associated with better survival.
• Limitations the authors state:
  • The HA assay could not tell apart HA molecules of different sizes, which matters because HA's function depends on its size.
  • Tumour material was not available to explore the source of the HA.
  • The short half-life of HA in blood and the number of serum samples with undetectable HA may have confounded the analysis of the effusion-to-serum ratio.
  • Whether a combination of markers outperforms mesothelin alone may depend heavily on which control groups are chosen for comparison.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Effusion, Hyaluronic Acid, Malignant Mesothelioma, Prognosis, Biomarker, Lung Cancer, Mesothelin, Biphasic Mesothelioma.

Related studies

• Utility of hyaluronic acid in pleural fluid for differential diagnosis of pleural effusions: likelihood ratios for malignant mesothelioma — S. Atagi, M. Ogawara, et al. (1997)
• Serum mesothelin has a higher diagnostic utility than hyaluronic acid in malignant mesothelioma — B. Grigoriu, B. Chahine, et al. (2009)
• Hyaluronic acid in the pleural fluid of patients with malignant pleural mesothelioma — N. Fujimoto, K. Gemba, et al. (2013)
• Is serum hyaluronic acid level useful for evaluating the clinical course of malignant mesothelioma of the tunica vaginalis? — K. Haga, N. Shinohara, et al. (1999)
• Histochemical demonstration of hyaluronic acid in pleural mesotheliomas — J.C. Wagner, D.E. Munday, et al. (1962)
• Clinical significance of the immunometric measurements of hyaluronic acid — E.H. Cooper, B.J. Rathbone (1990)

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